Spiro compounds

ABSTRACT

Spiro compounds of the general formula (I):whereinAr1 represents an optionally substituted aryl or heteroaryl;n represents 0 or 1;T, U, V and W each represent a nitrogen atom or an optionally substituted methine group, wherein at least two of which represent said methine group;X represents nitrogen;Y represents an optionally substituted imino or oxygen atom, which exhibit neuropeptide Y receptor (NPY) antagonistic activities and are useful as agents for the treatment of various diseases related to NPY, for example, cardiovascular disorders, central nervous system disorders, metobolic diseases and the like.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is useful in medical fields. In more detail, novelSpiro compounds of this invention are useful as neuropeptide Y receptorantagonists and as agents for the treatment of various kinds ofcardiovascular disorders, central nervous system disorders, metabolicdiseases, and the like.

2. Description of the Prior Art

Neuropeptide Y (hereinafter referred to as NPY), a peptide consisting of36 amino acids, was first isolated from porcine brain by Tatemoto et al.in 1982 [Nature, 296: 659 (1982)]. NPY is widely distributed in centralnervous system and peripheral nervous system and plays various roles asone of the most abundant peptide in the nervous system. That is, NPYacts as an orexigenic substance in the central nervous system andmarkedly promotes fat accumulation via the mediation of the secretion ofvarious hormones or the action of the nervous system. It is known thatthe continuous intracerebroventricular administration of NPY inducesobesity and insulin resistance based on these actions (InternationalJournal of Obesity, vol.19: 517 (1995); Endocrinology, vol.133: 1753(1993)). It is also known that NPY has central effects, such asdepression, anxiety, schizophrenia, pain, dementia and the like (Drugs,vol. 52, 371(1996). Further, in the periphery, NPY coexists withnorepinephrine in sympathetic ending and is involved in the tonicity ofthe sympathetic nervous system. It is known that peripheraladministration of NPY causes vasoconstriction and enhances theactivities of other vasoconstrictive substances such as norepinephrine(British Journal of Pharmacology, vol.95: 419 (1988)). It is alsoreported that NPY could participate in the development of cardiachypertrophy as a result of the sympathic stimulation (ProceedingNational Academic Science USA, Vol. 97, 1595(2000)).

On the other hand, it is reported that NPY is also involved in thesecretory function of sexual hormones and growth hormone, sexualbehavior and reproductive function, gastro-intestinal motility,bronchoconstriction, inflammation and alcohol preference (Life Science,vol. 55, 551(1994); The Journal of Allergy and Immunology, vol. 101,S345(1998); Nature, vol. 396, 366(1998)).

NPY has a variety of pharmacological effects which result from NPYbinding to the NPY receptors. Other NPY related peptides, includingpeptide YY and pancreatic polypeptide also bind to the NPY receptors. Itis known that these pharmacological effects are mediated by the actionof, at least, five receptor subtypes with or without synergisticinteractions. (Trends in Neuroscience, vol.20, 294(1997)).

Y1: It is reported that the central effect mediated by NPY Y1 receptorincludes the remarkable orexigenic effect (Endocrinology, vol. 137,3177(1996); Endocrinology, vol. 141, 1011(2000)). Further, the Y1receptor is reported to be involved in anxiety and pain (Nature, Vol.259, 528(1993); Brain Research, vol. 859, 361(2000)). In addition, thepressor effects mediated by the strong action of vasoconstriction in theperiphery by NPY is also reported to be mediated by Y1 (FEBS Letters,vol. 362, 192(1995); Nature Medicine, vol. 4, 722(1998)).

Y2: It is known that the inhibitory effect on the release of variousneurotransmitters in the sympathetic nerve endings is mediated by theNPY Y2 receptor (British Journal of Pharmacology, vol. 102, 41(1991);Synapse, vol. 2, 299(1988)). In periphery, NPY causes constriction ofblood vessel or vas deferens directly or via the control of release ofvarious neurotransmitters (The Journal of Pharmacology and ExperimentalTherapeutics, vol. 261, 863(1992); British Journal of Pharmacology, vol.100, 190(1990)). In addition, inhibition of lipolysis in adipose tissuesis known (Endocrinology, vol. 131, 1970(1992)). Further, the inhibitionof ion secretion in the gastrointestinal tract is reported (BritishJournal of Pharmacology, vol. 101 247(1990)).

On the other hand, the inhibitory effect on the central nervous systemfunctions such as memory and anxiety is also reported (Brain Research,vol. 503, 73(1989); Peptides, vol. 19, 359(1998)).

Y3: It is reported that NPY Y3 receptor is mainly located at brainstemand in the heart and is related to regulation of blood pressure andheart rate (The Journal of Pharmacology and Experimental Therapeutics,vol. 258, 633(1991); Peptides, vol. 11, 545(1990)). Further, it is knownthat the Y3 receptor is involved in the control of catecholaminesecretion in adrenal gland ((The Journal of Pharmacology andExperimental Therapeutics, vol. 244, 468(1988); Life Science, vol. 50,PL7(1992)).

Y4: NPY Y4 receptor has high affinity for pancreatic polypeptide. Therelated pharmacological effects reported to be mediated by the Y4receptor include the inhibition of pancreatic secretion and thegastro-intestinal motility (Gastroenterology, vol.85, 1411(1983)).Further, it is reported that NPY enhances the secretion of the sexualhormone in the central nervous system (Endocrinology, vol. 140,5171(1999)).

Y5: The effect mediated by NPY Y5 receptor includes feeding stimulationand accumulation of fat (Nature, vol. 382, 168(1996)); American Journalof Physiology, vol. 277, R1428(1999)). It is reported that the NPY Y5receptor also mediates some CNS effects, such as seizure and epilepsy,or pain and the morphine withdrawal symptoms (Natural Medicine, vol. 3,761(1997); Proceeding Academic Science USA, vol. 96, 13518(1999); TheJournal of Pharmacology and Experimental Therapetics, vol. 284,633(1998)). In the periphery, the Y5 receptor is reported to be involvedin diuresis and hypoglicemic effect caused by NPY (British Journal ofPharmacology, vol.120, 1335(1998); Endocrinology, vol.139, 3018(1998)).NPY is also reported to enhance cardiac hypertrophy as a result of thesympathic accentuation (Proceeding National Academic Science USA, Vol.97, 1595(2000)).

The effects of NPY occur by binding to the NPY receptors in the centralor peripheral nervous system. Therefore, the action of NPY can beprevented by blocking the binding to NPY receptors. Substancesantagonize NPY binding to NPY receptors may be useful for theprophylaxis or treatment of various diseases related to NPY, such ascardiovascular disorders (for example hypertension, nephropathy, heartdisease, vasospasm), central nervous system disorders (for examplebulimia, depression, anxiety, seizure, epilepsy, dementia, pain,alcoholism, drug withdrawal), metabolic diseases (for example obesity,diabetes, hormone abnormality), sexual and reproductive dysfunction,gastro-intestinal motility disorder, respiratory disorder, inflammationor glaucoma and the like (Trends in Pharmacological Sciences, 15: 153(1994); Life Science,. 55, 551(1994); Drugs, vol. 52, 371(1996); TheJournal of Allergy and Immunology, vol. 101, S345(1998); Nature, vol.396, 366(1998); The Journal of Pharmacology and ExperimentalTherapeutics, vol. 284, 633(1998); Trends in Pharmacological Science,vol. 20, 104(1999); Proceeding National Academic Science USA, vol. 97,1595(2000)).

Recently, according to the investigation of the present inventors, ithas been found that some kind of NPY receptor antagonist is useful inthe prophylaxis or treatment of hypercholesterolemia, hyperlipidemia andarteriosclerosis [International application publication WO99/27965].

SUMMARY OF THE INVENTION

The object of the present invention is to provide novel medicines whichexhibit NPY antagonistic activities.

The present inventors have discovered that the compounds of the generalformula (I):

wherein Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of—Q—Ar²;

Ar² represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, loweralkoxy, halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, loweralkanoyl and aryl;

n represents 0 or 1;

Q represents a single bond or carbonyl;

T, U, V and W represent independently nitrogen atom or methine groupwhich may have a substituent selected from the group consisting ofhalogen, lower alkyl, hydroxy and lower alkoxy, where at least two ofthem represent the said methine group;

X represents methine group or nitrogen;

Y represents imino which may be substituted with lower alkyl, or oxygen;

exhibit NPY antagonistic activities and is useful as a therapeutic agentfor treatment of various diseases associated with NPY, therebycompleting the present invention.

Compounds of the present invention (I) are useful as agents for thetreatment of various diseases related to NPY, that is, for examplecardiovascular disorders (for example hypertension, nephropathy, heartdisease, vasospasm, arteriosclerosis), central nervous system disorders(for example bulimia, depression, anxiety, seizure, epilepsy, dementia,pain, alcoholism, drug withdrawal), metabolic diseases (for exampleobesity, diabetes, hormone abnormality, hypercholesterolemia,hyperlipidemia), sexual and reproductive dysfunction, gastro-intestinaldisorder, respiratory disorder, inflammation, or glaucoma, and the like.

More particularly, compounds of this invention (I) is useful as agentsfor the treatment of bulimia, obesity, diabetes, and the like.

The present invention refers to compounds of the general formula (I),the salts or esters thereof, and the process for production and use.

In another embodiment, the present invention is related to theintermediate for producing the compound represented by the generalformula (I). Specifically, it is related to the compound represented bythe general formula (VI-1):

wherein t, u, v and w represent independently nitrogen atom or methinegroup which may have a substituent selected from the group consisting ofhalogen, lower alkyl, lower alkoxy and optionally protected hydroxy,where at least two of them represent the said methine group.

DETAILED DESCRIPTION OF THE INVENTION

The means of terms used in the present specification are defined andmore detailed description of this invention is shown in the following.

“Halogen atom” refers to fluorine atom, chlorine atom, bromine atom andiodine atom.

“Lower alkyl” refers to a straight- or branched-chain alkyl group of C1to C6, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.

“Halo(lower)alkyl” refers to the aforesaid lower alkyl substituted with1 or more than 2, preferably 1 to 3 aforesaid halogen atoms identicallyor differently at the substitutable, arbitrary positions, for example,fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,1,2-difluoroethyl, chloromethyl, 2-chloroethyl, 1,2-dichloroethyl,bromomethyl, iodomethyl, and the like.

“Hydroxy(lower)alkyl” refers to the aforesaid lower alkyl substitutedwith 1 or more than 2, preferably 1 or 2 hydroxy groups at thesubstitutable, arbitrary positions, for example, hydroxymethyl,2-hydroxyethyl, 1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl,3-hydroxypropyl, and the like.

“Cyclo(lower)alkyl” refers to a cycloalkyl group of C3to C6, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“Lower alkenyl” refers to a straight- or branched-chain alkenyl group ofC2 to C6, for example, vinyl, 1-propenyl, 2-propenyl, isopropenyl,3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl,1-methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl,2-methyl-1-propenyl, 3-methyl-2-butenyl, 4-pentenyl, and the like.

“Lower alkoxy” refers to a straight- or branched-chain alkoxy group ofC1 to C6, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy,isohexyloxy, and the like.

“Halo(lower)alkoxy” refers to the aforesaid lower alkoxy substitutedwith 1 or more than 2, preferably 1 to 3 aforesaid halogen atomsidentically or differently at the substitutable, arbitrary positions,for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy,2-fluoroethoxy, 1,2-difluoroethoxy, chloromethoxy, 2-chloroethoxy,1,2-dichloroethoxy, bromomethoxy, iodomethoxy, and the like.

“Lower alkylthio” refers to a straight- or branched-chain alkylthiogroup of C1 to C6, for example, methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, isobutylthio, tert-butylthio,pentylthio, isopentylthio, hexylthio, isohexylthio, and the like.

“Lower alkanoyl” refers to an alkanoyl group containing the aforesaidlower alkyl, that is, an alkanoyl group of C2 to C7, for example acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and thelike.

“Lower alkoxycarbonyl” refers to an alkoxycarbonyl group containing theaforesaid lower alkoxy, that is, an alkoxycarbonyl group of C2 to C7,for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, and the like.

“Lower alkylene optionally substituted with oxo” refers to a straight-or branched-chain alkylene group of C2 to C6 which may be substitutedwith 1 or more than 2, preferably 1 oxo group at a substitutable,arbitrary position, for example, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, 1-oxoethylene, 1-oxotrimethylene,2-oxotrimethylene, 1-oxotetramethylene, 2-oxotetramethylene, and thelike.

“Aryl” includes phenyl, naphthyl, and the like.

“Heteroaryl” refers to 5- or 6-membered monocylic heteroaromatic groupwhich contains 1 or more than 2, preferably 1 to 3 hetero atomsidentically or differently selected from the group of oxygen atom,nitrogen atom and sulfur atom; or condensed heteroaromatic group, wherethe aforesaid monocylic heteroaromatic group is condensed with theaforesaid aryl group, or with the identified or different aforesaidmonocylic heteroaromatic group each other, for example, pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, purinyl,quinolyl, isoquinolyl, phthalazyl, naphthylidinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, pyrido[3,2-b]pyridyl, and thelike.

“Lower alkylamino” refers to an amino group mono-substituted with theaforesaid lower alkyl, for example, methylamino, ethylamino,propylamino, isopropylamino, butylamino, sec-butylamino,tert-butylamino, and the like.

“Di-lower alkylamino” refers to an amino group di-substituted withidentical or different aforesaid lower alkyl, for example,dimethylamino, diethylamino, ethylmethylamino, dipropylamino,methylpropylamino, diisopropylamino, and the like.

The salts of compounds of formula (I) refer to the pharmaceuticallyacceptable and common salts, for example, base addition salt to carboxylgroup when the compound has a carboxyl group, or acid addition salt toamino or basic heterocyclyl when the compound has an amino or basicheterocyclyl group, and the like.

Aforesaid base addition salts include salts with alkali metals (forexample sodium, potassium); alkaline earth metals (for example calcium,magnesium); ammonium or organic amines (for example trimethylamine,triethylamine, dicyclohexylamine, ethanolamine, diethanolamine,triethanolamine, procaine, N,N′-dibenzylethylenediamine), and the like.

Aforesaid acid addition salts include salts with inorganic acids (forexample hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid,perchloric acid), organic acids (for example maleic acid, fumaric acid,tartaric acid, citric acid, ascorbic acid, trifluoroacetic acid),sulfonic acids (for example methanesulfonic acid, isethionic acid,benzenesulfonic acid, p-toluenesulfonic acid), and the like.

The esters of compounds of formula (I) refer to, for example, thepharmaceutically acceptable, common esters on carboxyl group when thecompound has a carboxyl group, for example, esters with lower alkyls(for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl,cyclopentyl), aralkyls (for example benzyl, phenethyl), lower alkenyls(for example allyl, 2-butenyl), lower alkoxy (lower) alkyls (for examplemethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl), lower alkanoyloxy (lower)alkyls (for example acetoxymethyl, pivaloyloxy-methyl,1-pivaloyloxyethyl), lower alkoxycarbonyl(lower)alkyls (for examplemethoxycarbonylmethyl, isopropoxycarbonylmethyl), carboxy-(lower)alkyls(for example carboxymethyl), lower alkoxycarbonyloxy-(lower)alkyls (forexample 1-(ethoxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl),carbamoyloxy(lower)alkyls (for example carbamoyloxymethyl), phthalidylgroup, (5-substituted-2-oxo-1,3-dioxol-4-yl)methyl (for example(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl), and the like.

“An agent for treatment” refers to a medicament which is employed forthe treatment and/or prophylaxis of various diseases.

In order to disclose the aforesaid compounds of the general formula (I)more detailed, the various symbols used in the formula (I) are explainedin more detail by the use of preferred embodiments.

Ar¹ represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl,lower alkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio,carboxyl, lower alkanoyl, lower alkoxycarbonyl, lower alkyleneoptionally substituted with oxo, and a group represented by formula of—Q—Ar².

“Aryl or heteroaryl which may be substituted, the substituent beingselected from the group consisting of halogen, nitro, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl,lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkylene optionally substitutedwith oxo, and a group represented by formula of —Q—Ar²” refers tounsubstituted aforesaid aryl or aforesaid heteroaryl, or the aforesaidaryl or aforesaid heteroaryl which has substituent(s) at thesubstitutable, arbitrary position(s). The aforesaid substituent can be,identically or differently, one or more than 2, preferably 1 or 2selected from the group consisting of halogen, nitro, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, cyclo(lower)alkyl, lower alkenyl,lower alkoxy, halo(lower)alkoxy, lower alkylthio, carboxyl, loweralkanoyl, lower alkoxycarbonyl, lower alkylene optionally substitutedwith oxo, and a group of formula: —Q—Ar².

Halogen atom as the aforesaid substituent includes fluorine atom,chlorine atom, and the like preferably.

Lower alkyl as the aforesaid substituent includes methyl, ethyl, propyl,isopropyl, and the like preferably.

Halo(lower)alkyl as the aforesaid substituent includes difluoromethyl,trifluoromethyl, and the like preferably.

Hydroxy(lower)alkyl as the aforesaid substituent includes hydroxymethyl,2-hydroxyethyl, 1-hydroxy-1-methylethyl, and the like preferably.

Cyclo(lower)alkyl as the aforesaid substituent includes cyclopropyl,cyclobutyl, and the like preferably.

Lower alkenyl as the aforesaid substituent includes vinyl, 1-propenyl,2-methyl-1-propenyl, and the like preferably.

Lower alkoxy as the aforesaid substituent includes methoxy, ethoxy, andthe like preferably.

Halo(lower)alkoxy as the aforesaid substituents includes fluoromethoxy,difluoromethoxy, trifluoromethoxy, and the like preferably.

Lower alkylthio as the aforesaid substituent includes methylthio,ethylthio, and the like preferably.

Lower alkanoyl as the aforesaid substituent includes acetyl, propionyl,and the like preferably.

Lower alkoxycarbonyl as the aforesaid substituent includesmethoxycarbonyl, ethoxycarbonyl, and the like preferably.

Lower alkylene optionally substituted with oxo as the aforesaidsubstituent includes 1-oxotetramethylene, and the like preferably.

In a group of formula: —Q—Ar² as the aforesaid substituent, Ar²represents aryl or heteroaryl which may be substituted, the substituentbeing selected from the group consisting of halogen, cyano, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy,halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl; Q represents a single bond or carbonyl.

“Aryl or heteroaryl which may be substituted, the substituent beingselected from the group consisting of halogen, cyano, lower alkyl,halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy, lower alkoxy,halo(lower)alkoxy, lower alkylamino, di-lower alkylamino, lower alkanoyland aryl” refers to unsubstituted aforesaid aryl or aforesaidheteroaryl, or the aforesaid aryl or aforesaid heteroaryl which hassubstituent(s) at the substitutable, arbitrary position(s). Theaforesaid substituent can be, identically or differently, one or notless than 2, preferably 1 or 2 selected from the group consisting ofhalogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl.

Halogen atom as the aforesaid substituent includes, preferably, fluorineatom, chlorine atom, and the like.

Lower alkyl as the aforesaid substituent includes, preferably, methyl,ethyl, propyl, isopropyl, and the like.

Halo(lower)alkyl as the aforesaid substituent includes, preferably,difluoromethyl, trifluoromethyl, and the like.

Hydroxy(lower)alkyl as the aforesaid substituent includes, preferably,hydroxymethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, and the like.

Lower alkoxy as the aforesaid substituent includes, preferably, methoxy,ethoxy, and the like.

Halo(lower)alkoxy as the aforesaid substituent includes, preferably,fluoromethoxy, difluoromethoxy, trifluoromethoxy, and the like.

Lower alkylamino as the aforesaid substituent includes, preferably,methylamino, ethylamino, and the like.

Di-lower alkylamino as the aforesaid substituent includes, preferably,dimethylamino, diethylamino, and the like.

Lower alkanoyl as the aforesaid substituent includes, preferably,acetyl, propionyl, and the like.

Aryl as the aforesaid substituent includes, preferably, phenyl, and thelike.

The substituent(s) of Ar² include, preferably, halogen, cyano, loweralkyl, halo(lower)alkyl, hydroxy(lower)alkyl, hydroxy,halo(lower)alkoxy, and the like.

Aryl in Ar²includes, preferably, phenyl, and the like and heteroarylincludes imidazolyl, pyridyl, benzofuranyl, quinolyl, and the like.

Consequently, a group of formula: —Q—Ar² includes, for example, phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-fluoro-5-methylphenyl,3-fluoromethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-fluoromethoxyphenyl,3-difluoromethoxyphenyl, 3-(2-hydroxyethyl)phenyl,3-hydroxymethylphenyl, 3-(1-hydroxy-1-methylethyl)phenyl,3-hydroxyphenyl, 4-hydroxyphenyl, 2-imidazolyl, 1-ethyl-2-imidazolyl,1,2,4-thiadiazol-5-yl, 1,3,4-thiadiaol-2-yl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-ethyl-4-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl,4-benzo[b]furanyl, 5-benzo[b]furanyl, 7-benzo[b]furanyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 8-quinolyl, benzoyl,2-pyridylcarbonyl, and the like, and preferably, phenyl, 2-fluorophenyl,3-fluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-cyanophenyl, 3-trifluoromethylphenyl, 3-difluoromethoxyphenyl,3-(2-hydroxyethyl)phenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,1-ethyl-2-imidazolyl, 2-pyridyl, 7-benzo[b]furanyl, 2-quinolyl,3-quinolyl, benzoyl, 2-pyridylcarbonyl, and the like.

The substituent of Ar¹ includes, preferably, halogen, lower alkyl,halo(lower)alkyl, lower alkenyl, lower alkanoyl, lower alkyleneoptionally substituted with oxo, and a group of formula: —Q—Ar², and thelike.

Aryl in Ar¹ includes, preferably, phenyl, and the like and heteroaryl ofAr¹ includes pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl,isoxazolyl, 1,2,3-triazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, 1,2,4-triazinyl, benzoxazolyl, benzothiazolyl, quinolyl,pyrido[3,2-b]pyridyl, and the like.

Consequently, Ar¹ includes, for example, 3-fluorophenyl, 4-fluorophenyl,3,4-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl,4-acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl,4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl,3-(2-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(2-pyridyl)phenyl,4-(3-pyridyl)phenyl, 4-(2-ethyl-4-pyridyl)phenyl,4-(4-pyrimidinyl)phenyl, 4-benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl,1-phenyl-3-pyrrolyl, 1-phenyl-4-imidazolyl,1-(2-fluorophenyl)-4-imidazolyl, 1-(3-fluorophenyl)-4-imidazolyl,1-(4-fluorophenyl)-4-imidazolyl, 1-(2,3-difluorophenyl)-4-imidazolyl,1-(2,4-difluorophenyl)-4-imidazolyl,1-(3,5-difluorophenyl)-4-imidazolyl, 1-(3-chlorophenyl)-4-imidazolyl,1-(2-cyanophenyl)-4-imidazolyl, 1-(3-cyanophenyl)-4-imidazolyl,1-(4-cyanophenyl)-4-imidazolyl,1-(3-trifluoromethylphenyl)-4-imidazolyl,1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl,1-[3-(1-hydroxy-1-methylethyl)phenyl]-4-imidazolyl,1-(3-methoxyphenyl)-4-imidazolyl,1-(2-difluoromethoxyphenyl)-4-imidazolyl,1-(3-difluoromethoxyphenyl)-4-imidazolyl,1-(4-difluoromethoxy-phenyl)-4-imidazolyl, 1-(2-pyridyl)-4-imidazolyl,1-(4-benzo[b]furanyl)-4-imidazolyl, 1-(5-benzo[b]furanyl)-4-imidazolyl,1-(7-benzo[b]furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-imidazolyl,1-(3-quinolyl)-4-imidazolyl, 1-(4-quinolyl)-4-imidazolyl,1-(5-quinolyl)-4-imidazolyl, 1-(6-quinolyl)-4-imidazolyl,1-(8-quinolyl)-4-imidazolyl, 1-phenyl-3-pyrazolyl, 5-phenyl-3-pyrazolyl,1-phenyl-4-pyrazolyl, 1-(2-fluorophenyl)-3-pyrazolyl,5-(2-fluorophenyl)-3-pyrazolyl, 5-(3-fluorophenyl)-3-pyrazolyl,1-(3-fluorophenyl)-4-pyrazolyl, 1-(4-fluorophenyl)-3-pyrazolyl,5-(4-fluorophenyl)-3-pyrazolyl, 5-(2-chlorophenyl)-3-pyrazolyl,5-(3-chlorophenyl)-3-pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl,5-(2-difluoromethoxyphenyl)-3-pyrazolyl,5-(3-difluoromethoxyphenyl)-3-pyrazolyl, 2-methyl-5-phenyl-3-pyrazolyl,5-(2-pyridyl)-3-pyrazolyl, 5-(2-quinolyl)-3-pyrazolyl,5-(3-quinolyl)-3-pyrazolyl, 4-phenyl-2-thiazolyl, 5-phenyl-2-thiazolyl,5-(3-chlorophenyl)-2-thiazolyl, 5-(4-chlorophenyl)-2-thiazolyl,5-(4-methoxyphenyl)-2-thiazolyl, 5-(2-pyridyl)-2-thiazolyl,2-phenyl-4-thiazolyl, 4-phenyl-2-oxazolyl, 5-phenyl-2-oxazolyl,4-(2-fluoromethoxyphenyl)-2-oxazolyl,4-(3-fluoromethoxyphenyl)-2-oxazolyl, 5-phenyl-3-isoxazolyl,3-phenyl-5-isoxazolyl, 3-(2-chlorophenyl)-5-isoxazolyl,3-(3-chlorophenyl)-5-isoxazolyl, 3-(4-chlorophenyl)-5-isoxazolyl,3-(2-pyridyl)-5-isoxazolyl, 2-phenyl-1,2,3-triazol-4-yl,5-phenyl-1,2,4-thiadiazol-3-yl, 5-phenyl-1,3,4-thiadiazol-2-yl,5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl,5-(2-pyridyl)-1,3,4-thiadiazol-2-yl,5-(2-ethyl-4-pyridyl)-1,3,4-thiadiazol-2-yl, 5-phenyl-2-pyridyl,6-phenyl-3-pyridyl, 2-phenyl-4-pyridyl, 5-(2-pyridyl)-2-pyridyl,5-benzoyl-2-pyridyl, 6-benzoyl-3-pyridyl, 5-chloro-2-pyrazinyl,5-(2-methyl-1-propenyl)-2-pyrazinyl, 5-acetyl-2-pyrazinyl,5-propionyl-2-pyrazinyl, 5-phenyl-2-pyrazinyl,5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl,5-(1,2,4-thiadiazol-5-yl)-2-pyrazinyl,5-(1,3,4-thiadiazol-2-yl)-2-pyrazinyl, 5-(2-pyridyl)-2-pyrazinyl,5-(3-pyridyl)-2-pyrazinyl, 5-(5-pyrimidinyl)-2-pyrazinyl,5-(3-quinolyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl,5-(2-pyridylcarbonyl)-2-pyrazinyl, 5-acetyl-2-pyrimidinyl,5-acetyl-3-methyl-2-pyrimidinyl, 4-phenyl-2-pyrimidinyl,5-phenyl-2-pyrimidinyl, 6-phenyl-4-pyrimidinyl, 2-phenyl-5-pyrimidinyl,5-(2-fluorophenyl)-2-pyrimidinyl, 5-(3-fluorophenyl)-2-pyrimidinyl,5-(4-fluorophenyl)-2-pyrimidinyl, 5-(2-chlorophenyl)-2-pyrimidinyl,5-(3-chlorophenyl)-2-pyrimidinyl, 5-(4-chlorophenyl)-2-pyrimidinyl,5-(2-methylphenyl)-2-pyrimidinyl, 5-(3-methylphenyl)-2-pyrimidinyl,5-(2-fluoromethylphenyl)-2-pyrimidinyl,5-(3-fluoromethylphenyl)-2-pyrimidinyl,5-(2-trifluoromethylphenyl)-2-pyrimidinyl,5-(3-trifluoromethylphenyl)-2-pyrimidinyl,5-(4-trifluoromethylphenyl)-2-pyrimidinyl,5-(2-hydroxymethylphenyl)-2-pyrimidinyl,5-(3-hydroxymethylphenyl)-2-pyrimidinyl,5-(2-hydroxyphenyl)-2-pyrimidinyl, 5-(3-hydroxyphenyl)-2-pyrimidinyl,5-(2-methoxyphenyl)-2-pyrimidinyl, 5-(3-methoxyphenyl)-2-pyrimidinyl,5-(4-methoxyphenyl)-2-pyrimidinyl,5-(2-fluoromethoxyphenyl)-2-pyrimidinyl,5-(3-fluoromethoxyphenyl)-2-pyrimidinyl,5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl,5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl, 6-phenyl-3-pyridazinyl,6-phenyl-1,2,4-triazin-3-yl, 5-chloro-2-benzoxazolyl,5-fluoro-2-benzothiazolyl, 4-methyl-2-benzothiazolyl,2-methyl-5-benzothiazolyl, 4-methoxy-2-benzothiazolyl, 3-quinolyl,6-quinolyl, 7-methyl-2-quinolyl, 2-methyl-6-quinolyl,6-chloro-2-quinoxalinyl, pyrido[3,2-b]pyridin-2-yl,7-chloropyrido[3,2-b]pyridin-2-yl, 7-methylpyrido[3,2-b]pyridin-2-yl,7-trifluoromethylpyrido[3,2-b]pyridin-2-yl,7-difluoromethoxypyrido[3,2-b]pyridin-2-yl,7-acetylpyrido[3,2-b]pyridin-2-yl, and the like, preferably3,4-dichlorophenyl, 4-acetylphenyl, 5-oxo-5,6,7,8-tetrahydro-2-naphthyl,4-acetyl-3-trifluoromethylphenyl, 4-(1-ethyl-2-imidazolyl)phenyl,4-benzoylphenyl, 4-(2-pyridylcarbonyl)phenyl, 1-phenyl-3-pyrrolyl,1-phenyl-4-imidazolyl, 1-(2-fluorophenyl)-4-imidazolyl,1-(3,5-difluorophenyl)-4-imidazolyl, 1-(3-chlorophenyl)-4-imidazolyl,1-(3-cyanophenyl)-4-imidazolyl,1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl,1-(3-difluoromethoxyphenyl)-4-imidazolyl,1-(7-benzo[b]furanyl)-4-imidazolyl, 1-(2-quinolyl)-4-imidazolyl,1-(3-quinolyl)-4-imidazolyl, 1-phenyl-3-pyrazolyl, 5-phenyl-3-pyrazolyl,1-phenyl-4-pyrazolyl, 1-(3-fluorophenyl)-4-pyrazolyl,1-(4-fluorophenyl)-3-pyrazolyl, 5-(4-chlorophenyl)-3-pyrazolyl,5-(3-quinolyl)-3-pyrazolyl, 5-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl,5-(2-methyl-1-propenyl)-2-pyrazinyl, 5-phenyl-2-pyrazinyl,5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl,5-(2-pyridyl)-2-pyrazinyl, 5-benzoyl-2-pyrazinyl,5-phenyl-2-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl,5-(3-fluorophenyl)-2-pyrimidinyl, 5-(3-chlorophenyl)-2-pyrimidinyl,5-(3-trifluoromethyl-phenyl)-2-pyrimidinyl, 5-chloro-2-benzoxazolyl,4-methyl-2-benzothia-zolyl, 7-methyl-2-quinolyl,7-trifluoromethylpyrido[3,2-b]pyridin-2-yl, and the like, especially1-phenyl-3-pyrazolyl, 5-phenyl-3-pyrazolyl, 5-phenyl-2-pyrazinyl,5-(3-hydroxyphenyl)-2-pyrazinyl, 5-(4-hydroxyphenyl)-2-pyrazinyl,5-phenyl-2-pyrimidinyl, 5-(2-fluorophenyl)-2-pyrimidinyl,5-(3-fluorophenyl)-2-pyrimidinyl,7-trifluoro-methylpyrido[3,2-b]pyridin-2-yl, and the like.

n represents 0 or 1, 0 is preferable.

T, U, V and W represent independently nitrogen atom or methine which mayhave a substituent selected from the group consisting of halogen, loweralkyl, hydroxy and lower alkoxy, where at least two of them representthe said methine group.

“Methine which may have a substituent selected from the group consistingof halogen, lower alkyl, hydroxy and lower alkoxy” refers tounsubstituted methine or methine having a substituent which can beselected from the group consisting of halogen, lower alkyl, hydroxy andlower alkoxy.

Halogen atom as the aforesaid substituent includes preferably fluorineatom, chlorine atom, and the like.

Lower alkyl as the aforesaid substituent includes preferably methyl,ethyl, and the like.

Lower alkoxy as the aforesaid substituent includes preferably methoxy,ethoxy, and the like.

The aforesaid substituent include preferably halogen, and the like.

The preferred mode of T, U, V and W includes, for example, T, U, V and Ware independently methine optionally having the aforesaid substituent,preferably halogen; or one of T, U, V and W is nitrogen atom.

X represents methine or nitrogen.

Y represents imino which may be substituted with lower alkyl, or oxygen.

“Imino which may be substituted with lower alkyl” refers tounsubstituted imino or imino substituted with lower alkyl.

The aforesaid lower alkyl includes, preferably, methyl, ethyl, and thelike.

Y is preferably unsubstituted imino or oxygen, especially oxygen.

In more detail, a group of formula (15):

includes a group of formula (16):

and the like.

Preferred compounds of the general formula (I) are, for example,compounds of the general formula (I-a):

wherein R¹ represents hydrogen atom or halogen, Ar¹ has the aforesaidmeaning;

or compounds of the general formula (I-b):

wherein Ar¹, T, U, V and W have the aforesaid meanings.

With regard to the compound represented by the general formula (I-a),the preferred compounds are, f or example, the compounds, wherein thearyl group in Ar¹ is phenyl, or the heteroaryl group in Ar¹ isimidazolyl, pyrazolyl, isoxazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyrimidinyl, quinolyl or pyrido[3,2-b]pyridyl.

With regard to the compound represented by the general formula (I-b),the preferred compounds are, for example, the compounds, wherein thearyl group in Ar¹ is phenyl, or the heteroaryl group in Ar¹ is pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl,1,2,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl or 1,2,4-triazinyl.

Further, with regard to the compound represented by the general formula(I-b), the preferred compounds are, for example, the compounds, whereinone of T, U, V and W is a nitrogen atom and the more preferred compoundsare, for example, the compounds wherein V is a nitrogen atom and T, U aswell as W are an unsubstituted methine group.

Compounds of this invention may include stereoisomers such as opticalisomers, diastereoisomers and geometrical isomers, or tautomersdepending upon the mode of substituents. Compounds of this inventioninclude all the stereoisomers, tautomers and their mixtures.

For example, compounds of the general formula (I-b) includestereoisomers such as trans-form compound of the general formula (I-1b):

and cis-form compound of the general formula (I-2b):

trans form is preferable.

Also included within the scope of the invention are polymorphs, hydratesand solvates of the compounds of the instant invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. Thus, in themethods of treatment of the present invention, the term “administering”shall encompass the treatment of the various conditions described withthe compound specifically disclosed or with a compound which may not bespecifically disclosed, but which converts to the specified compound invivo after administration to the patient. Conventional procedures forthe selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985, which is incorporated by reference herein in itsentirety. Metabolites of these compounds include active species producedupon introduction of compounds of this invention into the biologicalmilieu.

The specific compound represented by the general formula (I) is, forexample,

N-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

N-(7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,

N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-[1-(2-quinolyl)-4-imidazolyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-(5-phenyl-2-thiazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,

N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-{1-[3-(2-hydroxyethyl)phenyl]-4-imidazoly}-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,

3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,

N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,

trans-N-(4-benzoylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-3′-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-3′-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-3′-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-N-(4-acetyl-3-trifluoromethylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

4-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

7-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[4-(3-fluoromethoxyphenyl)-2-oxazolyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(6-phenyl-1,2,4-triazin-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-(4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamideor

trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.

Among these compounds, the preferable compound is, for example,

3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,

trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,

trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(l-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,

trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamideortrans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.

The process for producing compounds of this invention is illustrated asfollows.

Compounds of this invention (I) can be synthesized, for example, by thefollowing processes for production or the processes shown in examples,but these embodiments are not intended to restrict the process forproducing compounds of this invention (I).

Production Process 1

A compound of the general formula (II):

wherein Ar^(1p) represents aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl, lower alkenyl,lower alkoxy, halo(lower)alkoxy, lower alkylthio, lower alkanoyl, loweralkoxycarbonyl, a group of formula: —Q^(p)—Ar^(2p), and an optionallyprotected, lower alkylene optionally substituted with oxo,hydroxy(lower)alkyl or carboxyl group;

Ar^(2p) represents aryl or heteroaryl which may be substituted, thesubstituent being selected from the group consisting of halogen, cyano,lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, di-loweralkylamino, lower alkanoyl, aryl, and an optionally protectedhydroxy(lower)alkyl, hydroxy or lower alkyl amino group;

Ar³ represents phenyl which may be substituted by halogen or nitro;

Q^(p) represents a single bond or optionally protected carbonyl; isreacted with a compound of the general formula (III):

wherein n, t, u, v, w and Y have the same meanings as mentioned above;

to provide a compound of the general formula (IV-1):

wherein Ar^(1p), n, t, u, v, w and Y have the same meanings as mentionedabove;

optionally followed by elimination of a protective group to give acompound of the general formula (I-1):

wherein Ar¹, n, T, U, V, W and Y have the same meanings as mentionedabove.

This production process refers to the process for producing a compoundof the general formula (I), wherein X is nitrogen, that is, a compoundof the general formula (I-1).

When a reactant has an amino, hydroxy, carboxyl, oxo, carbonyl, or thelike group which does not participate in the reaction, the reaction maybe carried out after protecting the amino, hydroxy, carboxyl, oxo,carbonyl, or the like group with an amino protecting group, hydroxyprotecting group, carboxyl protecting group, or oxo- orcarbonyl-protecting group, followed by deprotection after completion ofthe reaction.

“Amino protecting group” includes aralkyl (for example benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,benzhydryl, trityl); lower alkanoyl (for example formyl, acetyl,propionyl, butyryl, pivaloyl); benzoyl; arylalkanoyl (for examplephenylacetyl, phenoxyacetyl); lower alkoxycarbonyl (for examplemethoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,tert-butoxycarbonyl); aralkyloxycarbonyl (for example benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl); lower alkylsilyl (forexample trimethylsilyl, tert-butyldimethylsilyl); and the like,especially acetyl, pivaloyl, benzoyl, ethoxycarbonyl,tert-butoxycarbonyl, and the like.

“Hydroxy protecting group” includes lower alkyl (for example methyl,ethyl, propyl, isopropyl, tert-butyl); lower alkylsilyl (for exampletrimethylsilyl, tert-butyldimethylsilyl); lower alkoxymethyl (forexample methoxymethyl, 2-methoxyethoxymethyl); tetrahydropyranyl;trimethylsilylethoxymethyl; aralkyl (for example benzyl,p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl,trityl); acyl (for example formyl, acetyl), and the like, especiallymethyl, methoxymethyl, tetrahydropyranyl, trityl,trimethylsilylethoxymethyl, tert-butyldimethylsilyl, acetyl, and thelike.

“Carboxyl protecting group” includes lower alkyl (for example methyl,ethyl, propyl, isopropyl, tert-butyl); lower haloalkyl (for example2,2,2-trichloroethyl); lower alkenyl (for example 2-propenyl); aralkyl(for example benzyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl,trityl); and the like, especially methyl, ethyl, tert-butyl, 2-propenyl,benzyl, p-methoxybenzyl, benzhydryl, and the like.

“Oxo- or carbonyl-protecting group” includes acetal or ketal (forexample ethylene ketal, trimethylene ketal, dimethyl ketal), and thelike.

The reaction between a compound of the general formula (II) and acompound of the general formula (III) is usually carried out byemploying an equivalent to excessive mole, preferably an equivalent to1.5 moles of compound (III) based on 1 mole of compound (II).

The reaction is usually carried out in an inert solvent, and as theinert solvent, made is use of, for example, methylene chloride,chloroform, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide orthe mixture, and the like, preferably.

The aforesaid reaction may be preferably carried out in the presence ofbase, including organic bases (for example triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganicbases (for example sodium hydroxide, potassium hydroxide), and the like.

The amount of the aforesaid base employed is usually an equivalent toexcessive mole, preferably 1 to 5 moles based on 1 mole of a compound ofthe general formula (II).

Reaction temperature is usually −30° C. to 200° C. preferably 20° C. to100° C.

Reaction time is usually 5 minutes to 7 days, preferably 30 minutes to24 hours.

At the conclusion of the reaction, the crude product of a compound ofthe general formula (IV-1) can be obtained by usual treatment. Thusobtained compound (IV-1) is purified by the conventional method, or notpurified, if necessary followed by optional combination of eliminationreaction of amino-, hydroxy-, carboxyl-, oxo- and carbonyl-protectinggroup to give a compound of the general formula (I-1).

The elimination of protecting groups may be carried out depending uponthe kinds of the aforesaid protecting groups, the stability of a desiredcompound (I-1) and so on, for example, by the manner described in theliterature [Protective Groups in Organic Synthesis, T. W. Greene, JohnWiley & Sons, (1981)] or its similar manner, for example, solvolysisusing acid or base, that is, for example 0.01 mole to a large excess ofacid, preferably trifluoroacetic acid, formic acid, hydrochloric acid,or the like, or an equivalent mole to a large excess of base, preferablypotassium hydroxide, calcium hydroxide, or the like; chemical reductionusing metallic complex hydride, or the like; or catalytic reductionusing palladium-carbon catalyst, Raney nickel catalyst, or the like.

Production Process 2

A compound of the general formula (V):

Ar^(1p)—NH₂  (V)

wherein Ar^(1p) has the same meaning as mentioned above; is reacted witha carboxylic acid of the general formula (VI):

wherein n, t, u, v, w and Y have the same meanings as mentioned above;

or its reactive derivative to provide a compound of the general formula(IV-2):

wherein Ar^(1p), n, t, u, v, w and Y have the same meanings as mentionedabove; optionally followed by elimination of a protecting group to givea compound of the general formula (I-2):

wherein Ar¹, n, T, U, V, W and Y have the same meanings as mentionedabove.

This production process refers to the process for producing compounds ofthe general formula (I), wherein X is methine, that is, a compound ofthe general formula (I-2).

Reaction between a compound of the general formula (V) and a carboxylicacid of the general formula (VI) is usually carried out by employing 0.5mole to excessive moles, preferably 1 mole to 1.5 mole of carboxylicacid (VI) based on 1 mole of compound (V).

The reaction is usually carried out in an inert solvent, and preferableexamples of the inert solvent include methylene chloride, chloroform,tetrahydrofuran, dimethylformamide, pyridine or a mixture thereof, andthe like.

The aforesaid reaction is preferably carried out in the presence ofcondensing agents, for example N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,benzotriazol-1-yl-oxy-tris-(dimethylamino)phosphoniumhexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphate, bromotris-(dimethylamino)phosphoniumhexafluorophosphate, diphenylphosphoryl azide, 1,1′-carbonyldiimidazole,or the like.

The aforesaid condensing agent is usually employed at 1 mole toexcessive mole, preferably. 1 mole to 1.5 moles based on 1 mole ofcompound (VI).

Reaction temperature is usually −50° C. to 100° C. preferably −20° C. to50° C.

Reaction time is usually 30 minutes to 7 days, preferably 1 hour to 24hours.

A compound of formula (I-2) is also produced by reacting a compound ofthe general formula (V) with a reactive derivative of the carboxylicacid (VI) instead of the carboxylic acid (VI).

The reactive derivatives of carboxylic acid of the general formula (VI)include acid halides, mixed acid anhydrides, activated esters, activatedamides, and the like.

The acid halides of carboxylic acid of the general formula (VI) may beobtained by reacting a carboxylic acid of the general formula (VI) witha halogenating agent according to the conventional method. Halogenatingagent includes thionyl chloride, phosphorus trichloride, phosphoruspentachloride, phosphorus oxychloride, phosphorus tribromide, oxalylchloride, phosgene, and the like.

The mixed acid anhydrides of carboxylic acid of the general formula (VI)may be obtained by reacting a carboxylic acid of the general formula(VI) with alkyl chlorocarbonate (for example ethyl chlorocarbonate);aliphatic carboxylic acid chloride (for example pivaloyl chloride), andthe like according to the conventional method.

The activated esters of carboxylic acid of the general formula (VI) maybe obtained by reacting a carboxylic acid of the general formula (VI)with N-hydroxy compound (for example N-hydroxysuccinimide,N-hydroxyphthalimide, 1-hydroxybenzotriazole); phenol compound (forexample 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol,pentachlorophenol), or the like in the presence of a condensing agent(for example N,N′-dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide) according to theconventional method.

The activated amides of carboxylic acid of the general formula (VI) maybe obtained by reacting a carboxylic acid of the general formula (VI)with for example 1,1′-carbonyldiimidazole,1,1′-carbonylbis(2-methylimidazole), or the like according to theconventional method.

Reaction between a compound of the general formula (V) and a reactivederivative of the carboxylic acid of the general formula (VI) is usuallycarried out by employing 0.5 mole to excessive mole, preferably 1 moleto 1.5 moles of the reactive derivative of carboxylic acid (VI) based on1 mole of compound (V).

The reaction is usually carried out in an inert solvent, and preferableexamples of the inert solvent include methylene chloride, chloroform,tetrahydrofuran, dimethylformamide, pyridine or a mixture thereof, andthe like.

The aforesaid reaction proceeds in the absence of bases, but it ispreferable to carry out the reaction in the presence of bases to promotethe reaction smoothly.

The aforesaid bases include organic bases (for example triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganicbases (for example sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate), and thelike.

It is preferable to employ 1 mole to excessive mole of the aforesaidbase to 1 mole of a compound of the general formula (V). When theaforesaid base is liquid, the aforesaid base can also be used as asolvent.

Reaction temperature is usually −50° C. to 100° C. preferably −20° C. to50° C.

Reaction time is usually 5 minutes to 7 days, preferably 30 minutes to24 hours.

A compound of the general formula (I-2) can be produced by treating areaction mixture in the usual way after deprotection if the product hasa protecting group at the conclusion of the reaction, or by treating themixture directly in the usual way if the protective group is absent.

Elimination of the protecting groups and post-treatment, and the likecan be carried out according to the method described in the aforesaidproduction process 1.

Compounds of the general formula (I-1) or (I-2) may readily be isolatedand purified by the conventional separation technique, for example,solvent extraction, recrystallization, column chromatography,preparative thin layer chromatography, or/and the like.

These compounds may be converted into the pharmaceutically acceptablesalts or esters by the conventional method, on the contrary, theconversion of the salts or esters into free compounds may also becarried out according to the conventional method.

Compounds of the general formula (II), (III), (V) or (VI) arecommercially available, or are prepared according to the methodsdescribed in the literature [Japanese Patent Unexamined PublicationNo.94/263737-A, U.S. Pat. No. 3,301,857, J. Org. Chem, 40: 1427 (1975),International Patent Publication WO95/28389 or the like], or analogousmethods thereto or the methods shown below or in Examples, optionally incombination.

wherein L¹ represents halogen; Ar^(1p) and Ar³ have the same meanings asgiven above;

This process refers to a process for producing a compound of the generalformula (II). Compound (II) is prepared by reacting a compound of thegeneral formula (V) with a compound of the general formula 1 accordingto this process.

The reaction between a compound (V) and a compound 1 is usually carriedout by employing 0.5 mole to excessive mole, preferably an equivalent to1.5 moles of compound 1 based on 1 mole of compound (V).

The reaction is usually carried out in an inert solvent, and thepreferable examples of the inert solvent include methylene chloride,chloroform, tetrahydrofuran, ethyl ether, benzene, toluene,dimethylformamide or a mixture thereof, and the like.

It is preferable to carry out the reaction in the presence of bases. Theaforesaid bases include organic bases (for example triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine) or inorganicbases (for example sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate), and thelike.

It is preferable to employ an equivalent to excessive mole of theaforesaid base to 1 mole of a compound (V). When the aforesaid base isliquid, the aforesaid base can be used also as a solvent.

Reaction temperature is usually −78° C. to 100° C. preferably −20° C. to50° C.

Reaction time is usually 5 minutes to 7 days, preferably 30 minutes to24 hours.

Compounds of formula I are commercially available, or are preparedaccording to the conventional method, the methods described in Examples,or the like methods, optionally in combination.

wherein P¹ represents an amino protecting group;

R¹⁰ represents hydrogen, nitro, lower alkyl or lower alkoxy;

L¹, t, u, v and w have the same meanings as given above.

This process refers to a process for producing compounds of the generalformula (III-1). Compound (III-1) may so be prepared by the presentprocess that a compound of the general formula 2 is subjected todehydrogenated condensation with a compound of the general formula 3 togive a compound of the general formula 4, which is subjected to reactionwith a compound of the general formula 5 in the presence of a base toyield a compound of the general formula 6 and then the compound 6 iscyclized by an intra-molecular Heck reaction to give a compound of thegeneral formula a, and then the compound 7 is subjected to reduction,optionally followed by elimination of amino protecting group P¹.

Amino protecting group P¹ includes the amino protecting groups describedin the aforesaid production process 1.

A step for preparing compound A by dehydrogenated condensation ofcompound 2 with compound 3 is usually carried out in an inert solvent,for example benzene, toluene, or the like.

Reaction temperature is preferably from room temperature to the boilingpoint of a solvent used and reaction time is preferably from 30 minutesto 24 hours.

A step for preparing compound 6 from compound 4 is usually carried outin an inert solvent (for example benzene, toluene, methylene chloride,chloroform, acetonitrile, dimethylformamide) in the presence of base(for example triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine).

Reaction temperature is preferably from 0° C. to the boiling point of asolvent used and reaction time is preferably from 30 minutes to 24hours.

So-called intramolecular Heck reaction well known in the field oforganic chemistry can be applied to the step for preparing compound 7from compound 6.

The aforesaid step is usually carried out in an inert solvent (forexample benzene, toluene, tetrahydrofuran, acetonitrile,dimethylformamide, N-methylpyrrolidone) in the presence of palladiumcatalyst (for example palladium acetate, palladium chloride), phosphineligand (for example triphenylphosphine, tri-2-furylphosphine) and base(for example potassium carbonate, triethylamine), optionally additives(for example tetraethylammonium chloride).

Reaction temperature is preferably from room temperature to the boilingpoint of a solvent used in reaction and reaction time is preferably from30 minutes to 24 hours.

As a method for reduction in the step for preparing compound (III-1)from compound 7, for example catalytic reduction is preferable.

The catalytic reduction is usually carried out in an inert solvent (forexample methanol, ethanol, methylene chloride, chloroform,tetrahydrofuran, dimethylformamide, acetic acid) in the presence of acatalyst such as palladium-carbon at 1 to 50 atmospheric pressure ofhydrogen.

Reaction temperature is preferably from room temperature to the boilingpoint of a solvent used and reaction time is preferably from 30 minutesto 24 hours.

At the conclusion of the reaction, if a reaction product has aprotecting group, compound (III-1) can be prepared by elimination of theprotecting group.

Elimination of a protecting group can be carried out according to themethod described in the aforesaid production process 1.

This step may also be carried out by elimination of the protecting groupof compound 7, followed by reduction of the resulting compound.

Compounds of the general formula 2, 3 or 5 are commercially available,or may be prepared according to the conventional method, the methodsshown in Examples, or the like methods, optionally in combination.

wherein L² represents hydrogen or halogen;

Ph represents phenyl;

Y¹ represents oxygen or imino substituted with lower alkyl or aryl;

t, u, v and w have the same meanings as given above.

This production process refers to the process for preparing compound ofthe general formula (VI-1). The compound represented by the generalformula of (VI-1) is novel compound, which is not disclosed in theliterature. The compound can be produced according to the presentproduction process, that is, a compound of the general formula B issubjected to lithiation, reaction with compound 9 and lactonization withan acid, followed by deketalation to yield a compound of the generalformula 10; and 1) methylene group is introduced to the compound 10,which is followed by hydroboration to give a compound of the generalformula 11, and the compound is subjected to oxidation reaction, or 2)the compound 10 is reduced to give a compound of the general formula 12,which is subjected to introduction of a leaving group and thencyanization to give a compound of the general formula 13, followed byhydrolysis of the compound 13 at the cyano group.

Lithiation in the step preparing compound 10 from compound 8 is usuallycarried out by allowing compound 8 to be acted on by an organic lithiumreagent (for example n-butyllithium, lithium2,2,6,6-tetramethyl-piperidide) in an inert solvent (for exampletetrahydrofuran, diethyl ether).

Reaction temperature is usually from −120° C. to 0°C., preferably from−100° C. to −50° C. and reaction time is preferably from 1 hour to 4hours.

Reaction between the resulting lithio type and a ketone of the generalformula 9 is usually carried out in an inert solvent (for exampletetrahydrofuran, diethyl ether).

Reaction temperature is preferably from −100° C. to room temperature andreaction time is preferably from 10 minutes to 2 hours.

The resulting compound can be lactonized by treating with an acid (forexample hydrochloric acid, sulfuric acid).

Reaction temperature is preferably from 0° C. to the boiling point of asolvent used and reaction time is preferably from 30 minutes to 8 hours.

Compound 10 can be prepared by subjecting the resulting lactone type todeketalation according to the conventional method.

Reaction temperature is preferably from 50° C. to the boiling point of asolvent used and reaction time is preferably from 1 hour to 24 hours.

The method used for converting oxo group to hydroxymethyl group, whichis well known in the field of organic chemistry, can be applied to thestep for preparing compound 11 from compound 10 and the step is usuallycarried out by reacting compound 10 with for examplemethylenetriphenylphosphorane to introduce a methylene group, followedby hydroboration in an inert solvent (for example benzene, toluene,methylene chloride, chloroform, acetonitrile, tetrahydrofuran,dimethylformamide).

In both steps for introducing methylene group and for hydroboration,reaction temperature is preferably from 0° C. to the boiling point of asolvent used and reaction time is preferably from 30 minutes to 8 hours.

The method used for oxidizing hydroxymethyl group to carboxyl group,which is well known in the field of organic chemistry, can be applied tothe step for preparing compound (VI-1) from compound 11 and the step isusually carried out by using an oxidizing agent such as sodium periodateand a catalytic amount of ruthenium chloride, in an inert solvent (forexample benzene, toluene, methylene chloride, chloroform, acetonitrile,dimethylformamide).

Reaction temperature is preferably from 0° C. to the boiling point of asolvent used and reaction time is preferably from 30 minutes to 8 hours.

The method used for reducing oxo group to hydroxyl group, which is wellknown in the field of organic chemistry, can be applied to the step forpreparing compound 12 from compound 10 and the step is usually carriedout by using a reducing agent (for example sodium borohydride, lithiumborohydride), in an inert solvent (for example water, methanol, ethanol,tetrahydrofuran or a mixture thereof).

Reaction temperature is preferably from −20° C. to 50° C. and reactiontime is preferably from 10 minutes to 4 hours.

The method used for converting hydroxy group to cyano group, which iswell known in the field of organic chemistry, can be applied to the stepfor preparing compound 13 from compound 12 and the step is usuallycarried out by reacting compound 12 with for example methanesulfonylchloride, p-toluenesulfonyl chloride, or the like to convert hydroxygroup to a leaving group in the presence of base (for exampletriethylamine, pyridine), followed by reacting the resulting compoundwith a cyanide (for example sodium cyanide, potassium cyanide,tetraethylammonium cyanide, tetrabutylammonium cyanide).

The step for converting hydroxy group to a leaving group is usuallycarried out in an inert solvent (for example methylenechloride,chloroform, ethylacetate, acetonitrile, tetrahydrofuran,dimethylformamide). Reaction temperature is preferably from −20° C. toroom temperature and reaction time is preferably from 10 minutes to 8hours.

The step for reacting with a cyanide is usually carried out in an inertsolvent (for example tetrahydrofuran, dioxane, dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide). Reaction temperature ispreferably from 50° C. to 120° C. and reaction time is preferably from 2to 24 hours.

Hydrolysis of cyano group, which is well known in the field of organicchemistry, can be applied to the step for preparing compound (VI-1) byhydrolysis of the cyano group of compound 13and the step is usuallycarried out by using an acid (for example hydrochloric acid, sulfuricacid) or a base (for example sodium hydroxide, potassium hydroxide,calcium hydroxide), in a solvent (for example methanol, ethanol,tetrahydrofuran, dioxane, water or a mixture thereof).

Reaction temperature is preferably from 50° C. to the boiling point of asolvent used and reaction time is preferably from 1 to 48 hours.

Compounds of the general formula (VI-1) have two kinds of stereoisomersrepresented by the general formula (VI-1-a) or (VI-1-b):

wherein t, u, v and w have the same meanings as given above.

These stereoisomers can be separated from the mixture by theconventional method such as chromatography, fractionalrecrystallization, and the like.

Compounds of the general formula (VI-1-a) or (VI-1-b) can be prepared byusing an intermediate product which is obtained by separation of thestereoisomers of the general compound 11, 12 or 13.

Compounds of the general formula 8 or 9 are commercially available, orare prepared according to the conventional method, the methods describedin Examples, or the like methods, optionally in combination.

The utility of compounds of the present invention as a medicament isproved by describing NPY antagonistic activity, for example, in thefollowing pharmacological tests.

Pharmacological Test 1 (NPY Binding Inhibition Test)

cDNA sequence encoding human NPY Y5 receptor [International patentpublication number WO96/16542] was cloned into expression vectorspcDNA3, pRc/RSV (made by Invitrogen Inc.) and pCI-neo (made by PromegaInc.). This obtained expression vectors were transfected to host cellsCOS-7, CHO and LM(tk−) (American Type Culture Collection) by cationiclipid method [Proceedings of the National Academy of Sciences of theUnited States of America, 84: 7413(1987)] to give NPY Y5 receptorexpression cells.

A membrane sample prepared from the cells which expressed NPY Y5receptor was incubated together with a test compound and [¹²⁵I]peptideYY(NEN) (20,000 cpm) in an assay buffer (25 mM Tris buffer, pH7.4,containing 10 mM magnesium chloride, 1 mM phenylmethylsulfonyl fluoride,0.1% bacitracin and 0.5% bovine serum albumin) at 25° C. for 2 hours,then filtered through a glass filter GF/C and washed with 5 mM Trisbuffer (pH7.4) containing 0.3% BSA. The radioactivity of the cake on theglass filter was measured. Nonspecific binding was measured in thepresence of 1 μM peptideYY and a 50% Inhibitory Concentration (IC50) ofthe test compound against specific peptideYY binding was determined[Endocrinology, 131: 2090(1992)]. The results are summarized in Table 1.

[Table 1]

Inhibitory Activities on NPY Receptor Binding

Compounds IC50 (nM) Example 1 1.2 Example 9 0.72 Example 23 1.9 Example26 2.5 Example 32 0.91 Example 44 1.5 Example 50 0.48 Example 55 0.59

As shown above, compounds of this invention potently inhibited peptideYY(NPY homologue) binding to NPY Y5 receptors.

Pharmacological Test 2 (Antagonistic Effect on bPP-induced FeedingBehavior)

A guide cannula (external diameter 0.8 mm, internal diameter 0.5 mm,length 10 mm) was inserted stereotaxicly into the right lateralventricle of male SD rats (7-8 weeks old, 200-300 g) anesthetized withpentobarbital (single intraperitoneal administration of 50 mg/kg) andfixed by dental resin. The top of the cannula was located 0.9 mm behindbregma, 1.2 mm to the right of median line and 1.5 mm depth from thebrain surface so that, when injection needle is inserted into the guidecannula, the needle extends 2 mm beyond the tip of the guide cannula andreaches the lateral ventricle. After about 1-week recovery period,bovine pancreatic polypeptide (bPP, 5 μg/10 μL/head, 0.01M, pH7.4phosphate buffered saline solution containing 0.05% bovine serumalbumin) was injected into the lateral ventricle. A test compoundsuspended in aqueous 0.5% methylcellulose was administered orally 2hours before the administration of bPP and the food consumption wasmeasured 2 hours after administration of bPP.

Compounds of this invention significantly inhibited the increase in foodconsumption induced by bPP (NPY homologue) which was administered to thelateral ventricle.

Compounds of the general formula (I) can be administered orally orparenterally and may be formulated in the form suitable foradministration to provide an agent for treatment of various diseasesrelated to NPY, which include, for example, cardiovascular disorders(for example hypertension, nephropathy, heart disease, vasospasm,arteriosclerosis), central nervous system disorders (for examplebulimia, depression, anxiety, seizure, epilepsy, dementia, pain,alcoholism, drug withdrawal), metabolic diseases (for example obesity,diabetes, hormone abnormality, hypercholesterolemia, hyperlipidemia),sexual and reproductive dysfunction, gastro-intestinal motilitydisorder, respiratory disorder, inflammation or glaucoma and the like,preferably, bulimia, obesity, diabetes and the like. In clinical use,compounds of this invention can be administered after being formulated,together with pharmaceutically acceptable additives, into an appropriatepreparation according to the mode of administration. For said additives,those which are usually used in the field of pharmaceutical formulationmay be used, for example, gelatin, lactose, sucrose, titanium oxide,starch, crystalline cellulose, hydroxypropyl methylcellulose,carboxymethylcellulose, corn starch, microcrystalline wax, whitepetrolatum, magnesium methasilicate aluminate, anhydrous calciumphosphate, citric acid, sodium citrate, hydroxypropyl cellulose,sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acidester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone,magnesium stearate, light silicic anhydride, talc, vegetable oil, benzylalcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrinor hydroxypropyl cyclodextrin.

A mixture with said additives may be formulated in the form of solidpreparations (for example tablets, capsules, granules, powder,suppositories); or liquid preparations (for example syrups, elixirs,injections). Such preparations may be formulated according to techniqueswell-known in the art of pharmaceutical formulation. Liquid preparationsmay be in the form of preparations which are dissolved or suspended inwater or other appropriate media when used and especially injectablepreparations may be dissolved or suspended in physiological saline orglucose solution if necessary, optionally together with a buffer andpreservative.

Such preparations may contain 0.1 to 100 wt. %, preferably 1.0 to 60 wt.% of compounds of this invention and may also contain therapeuticallyeffective other compounds.

The compounds of the present invention can be used in combination withother agents useful for treating metabolic and/or feeding disorders. Theindividual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently individed or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating metabolic and/or feeding disorders includes in principleany combination with any pharmaceutical composition useful for treatingmetabolic and/or feeding disorders.

When compounds of this invention are used clinically, the dose andfrequency of dosage may be varied depending upon the sex, age, bodyweight, the degree of symptoms and the kind and range of the desiredtreatment effects. A daily dose for an adult is 0.01-100 mg/kg,preferably 0.03-3 mg/kg orally, or 0.001-10 mg/kg, preferably 0.001-0.1mg/kg parenterally, preferably in a single dose or in divided doses.

An ordinarily skilled physician, veterinarian or clinician can readilydetermine and prescribe the effective amount of the drug required toprevent, counter or arrest the progress of the condition.

EXAMPLES

The following examples are provided so that the present invention may bemore concretely illustrated but they should not be construed as limitingthe invention in any way.

Unless otherwise noted, melting point was measured by MP-S3 Model(manufactured by Yanagimoto Seisakusho) and disclosed in thisspecification without correction.

Example 1 Preparation ofN-(4-benzoylphenyl)-3-oxospiro[isoindoline-1.4′-piperidine]-1′-carboxamide

(1) Preparation ofN-benzyl-N-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-iodobenzamide

A mixture of N-tert-butoxycarbonyl-4-piperidone (1.11 g) and benzylamine(597 mg) dissolved in toluene (20 mL) was stirred at 100° C. for 3 hoursand then concentrated. Toluene (30 mL), o-iodobenzoyl chloride (1.13 g)and triethylamine (0.70 g) were added to the residue and the mixture wasstirred at 80° C. for 2 hours. The reaction mixture was poured intowater and extracted with ethyl acetate. The ethyl acetate layer wasdried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2)to give the subject compound (2.44 g).

(2) Preparation of2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydro-spiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one

ToN-benzyl-N-(1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-iodobenzamide(2.4 g) dissolved in acetonitrile, palladium acetate (80 mg),triphenylphosphine (187 mg), anhydrous K₂CO₃ (987 mg) andtetraethylammonium chloride (591 mg) were added and stirred at 80° C.for 6 hours. The reaction mixture was poured into water and extractedwith ethyl acetate. The ethyl acetate layer was dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to givethe subject compound (1.64 g).

(3) Preparation of2-benzyl-1′-tert-butoxycarbonylspiro[1H-isoindole-1,4′-piperidine]-3(2H)-one

To a solution of2-benzyl-1′-tert-butoxycarbonyl-1′,6′-dihydrospiro[1H-isoindole-1,4′(5′H)-pyridine]-3(2H)-one(1.0 g) in chloroform (20 mL), trifluoroacetic acid (20 mL) was addedand the mixture was stirred for 1 hour. The reaction mixture wasconcentrated. The residue was dissolved in methanol and hydrogenatedwith 4M hydrogen chloride/ethyl acetate in the presence of 20% palladiumcarbon at 1 atm of hydrogen for 14 hours. The catalyst was removed byfiltration and the filtrate was concentrated. To the residue, aqueous 1Nsodium hydroxide (5 mL), di-tert-butyl dicarbonate (655 mg) and dioxane(10 mL) were added and the mixture was stirred at room temperature for 4hours. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subjectcompound (200 mg).

(4) Preparation of spiro[1H-isoindole-1,4′-piperidine]-3(2H)-onehydrochloride

2-Benzyl-1′-tert-butoxycarbonylspiro[1H-isoindole-1,4′-piperidine]-3(2H)-one(200 mg) was added to metallic sodium (235 mg) in liquid ammonia (10 mL)and the mixture was stirred for 30 minutes. To the reaction mixture wasadded methanol, neutralized with a saturated ammonium chloride aqueoussolution and extracted with ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄ and concentrated. The residue dissolved inmethanol was stirred together with 4M hydrogen chloride/ethyl acetate at50° C. for 1 hour. The reaction solution was concentrated to give thesubject compound (591 mg).

¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 1.70-1.90 (2H, m), 2.00-2.20 (2H,m),3.00-3.20 (2H,m), 4.20-4.40 (2H, m), 7.40 (1H, d, J=7.5 Hz), 7.51 (1H,t, J=7.5 Hz), 7.59 (1H, t, J=7.5 Hz), 7.84 (1H, d, J=7.5 Hz).

(5) Preparation of phenyl N-(4-benzoylphenyl)carbamate

To 4-aminobenzophenone (1.97 g) dissolved in pyridine (50 mL), phenylchlorocarbonate (1.38 g) was added at 0° C. and the mixture was stirredat room temperature for 1 hour. The reaction mixture was poured intowater and extracted with ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄ and evaporated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to givethe subject compound (3.1 g).

(6) Preparation ofN-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide

A mixture of spiro[1H-isoindole-1,4′-piperidine]-3(2H)-one hydrochloride(48 mg), triethylamine (0.14 mL) and phenyl N-(4-benzoylphenyl)carbamate(58 mg) was stirred in chloroform at 80° C. for 2 hours. The reactionmixture was poured into water and extracted with chloroform. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=4/1 to 1/2) and crystallized from ethyl ether-hexane to give thesubject compound (49 mg) as colorless crystals (melting point 253° C.).

Compounds of Example 2 and 3 were obtained in the similar manner asExample 1-(6) by replacing phenyl N-(4-benzoylphenyl)carbamate used inExample 1-(6) by the corresponding materials, respectively.

Example 23-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide

melting point 286-287° C.

Example 3N-(7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide

melting point 194-196° C.

Example 4 Preparation ofN-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide

The subject compound was obtained in the similar manner as Example 1-(6)by replacing spiro[1H-isoindole-1,4′-piperidine]-3(2H)-one hydrochlorideby 2-methylspiro[1H-isoindole-1,4′-piperidine]-3(2H)-one hydrochloride.

melting point 154-156° C.

Example 5 Preparation ofN-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[iso-quinoline-1(2H),4′-piperidine]-1′-carboxamide

Spiro[isoquinoline-1(2H),4′-piperidine]-3(4H)-one hydrochloride (30 mg)and phenyl N-(4-benzoylphenyl)carbamate (37 mg) were dissolved indimethyl sulfoxide (2 mL) and stirred together with aqueous 10N sodiumhydroxide (12 μL) at room temperature for 30 minutes. The reactionmixture was poured into water and extracted with ethyl acetate (20 mL).The organic layer was washed with water (20 mL) and saturated salinesolution (20 mL), then dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=4/1 to 1/2) and recrystallized fromchloroform-acetone (1:3) to give the subject compound (81 mg) ascolorless crystals (melting point 241-243° C.).

Compounds of Example 6 to 21 were obtained in the similar manner asExample 1-(6) or Example 5 by usingspiro[isoquinoline-1(2H),4′-piperidine]-3(4H)-one hydrochloride andphenyl carbamate derivatives corresponding to the desired compounds.

Example 63,4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 237-239° C.

Example 73,4-Dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 216-218° C.

Example 8N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point>300° C.

Example 93,4-Dihydro-3-oxo-N-[1-(2-quinolyl)-4-imidazolyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 264-266° C.

Example 103,4-Dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 220.5-222.2° C.

Example 113,4-Dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 232.9-236.5° C.

Example 123,4-Dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H),4′-piperidine]1′-carboxamide

melting point 239-241° C.

Example 13N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 192-194° C.

Example 14N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 161-163° C.

Example 153,4-Dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 162-164° C.

Example 16N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point>300° C.

Example 17N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 255-258° C.

Example 183,4-Dihydro-3-oxo-N-(5-phenyl-2-thiazolyl)spiro[isoquinoline-1(2H)4′-piperidine]-1′-carboxamide

melting point>300° C.

Example 193,4-Dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 223-225° C.

Example 203,4-Dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 144-146° C.

Example 21N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide

melting point 256-258° C.

Example 22 Preparation ofN-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (48 mg), phenyl N-(4-benzoylphenyl)carbamate (58 mg) andtriethylamine (0.14 mL) in chloroform (5 mL) was stirred at 80° C. for 2hours. The reaction mixture was poured into water and extracted withchloroform (20 mL). The organic layer was washed with saturated salinesolution (20 mL), then dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethylether-hexane to give the subject compound (81 mg) as colorless crystals(

melting point 161-163° C.).

Example 23 Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

(1)Preparation of phenyl N-(5-phenyl-2-pyrazinyl)carbamate

Phenyl chlorocarbonate (15.05 mL) was added at 0° C. to a solution of2-amino-5-phenylpyrazine (17.12 g) in pyridine (200 mL). The mixture wasstirred at room temperature for 2 hours. To the reaction mixture wasadded water (200 mL) and ethyl ether (200 mL). The whole was stirred toprovide a suspension containing the subject compound as a crystal. Thecrystal was collected by filtration and further washed with ethyl ether(50 mL) and then dried under reduced pressure to provide the subjectcompound (24.57 g) as colorless crystals (melting point 192-198° C.,decomposed).

(2)Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form A)

A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (6.24 g, 26.6 mmol), phenylN-(5-phenyl-2-pyrazinyl)carbamate(7.59 g, 26.0 mmol) and triethylamine(18 mL, 180 mmol) in chloroform (200 mL) was stirred at 80° C. for 3hours. The reaction mixture was washed with saturated aqueous sodiumbicarbonate (100 mL). After the organic layer was washed with 10% citricacid aqueous solution (100 mL), 1N aqueous sodium hydroxide (100 mL) andthen saturated saline solution (100 mL), the organic layer was driedover anhydrous Na₂SO₄ and then concentrated. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=1/2) toprovide the subject compound as a colorless solid. The solid was washedwith diethyl ether (30 mL) to provide the subject compound (8.23 g) as acrude crystal. The crystal was dissolved in hot ethyl acetate (300 mL).After removal of about 100 mL of ethyl acetate by distillation, thewhite suspension began to occur. At this point the distillation wasstopped and the whole was cooled and then kept at room temperature for14 hours. The colorless prisms formed was collected by filtration, whichwas washed with heptane (20 mL). The obtained crystal was dried at 50°C. in vacuo for 6 hours to provide the subject compound (Crystal Form A)(5.17 g) as colorless prisms (melting point 210-211° C.).

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 8.160 4135 9.600 2607 11.680 1372 14.620194 15.320 1505 15.620 1321 15.880 2687 16.080 1711 16.420 3174 17.9401036 19.100 6232 19.600 878 20.280 206 20.860 813 21.300 3360 22.020 32822.740 1498 23.460 3782 23.820 549 24.420 1915 24.880 474 25.840 132926.360 515 28.480 433 29.260 248 30.860 692 32.140 246 34.300 112 39.160163

Above powder X-ray diffraction analysis data were measured by RINT1100(manufactured by Rigaku International Corporation) and analysis methodswere as follows:

X-ray radiation source: Cu,

tube voltage: 40 kV,

tube current: 30 mA,

monochromater: automatic monochromater,

mono receiving slit: 0.60 mm,

goniometer: Wide angle goniometer,

scan step: 0.02 deg.,

scan speed: 2.00 deg./min.,

divergence slit(DS): 1 deg.,

scattering slit: 1 deg.,

receiving slit (RS): 0.15 mm,

measured temperature: ambient temperature.

(3) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form A)—an alternative method for preparation

Crude crystals (2 g) prepared by the above procedure (2) was dissolvedunder heating into tetrahydrofuran (20 mL). After confirming completedissolution, the mixture was cooled to the room temperature by standingit at room temperature. Heptane (27 mL) was dropwise added to thetetrahydrofuran solution, followed by stirring at room temperature for15 hours. The yielded colorless crystals were collected by filtration,washed with heptane (5 mL) and dried in vacuum at 30° C. for 15 hours toobtain the above-identified compound in crystal form A (1.82 g).

(4) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form B)

Crude crystals (2 g) prepared by the above procedure (2) was dissolvedunder heating into dimethylformamide (6 mL). After confirming completedissolution, water (13 mL) was dropwise added at 80° C. and theresultant mixture was cooled to room temperature, followed by stirringfor 15 hours. The yielded colorless crystals were collected byfiltration at room temperature, washed with heptane (5 mL) and dried invacuum for 15 hours at room temperature to obtain 1.78 g of theabove-identified compound in the crystal form B as colorless prisms(melting point; 208° C. measured without correction by the use ofMelting Point B-545 distributed by Buchi Company).

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 7.300 211 9.540 555 13.340 619 14.320 84814.680 2435 15.620 7792 15.980 2307 16.400 6800 19.280 781 19.620 313719.920 1954 20.280 2234 20.900 4008 23.000 2311 24.060 3362 24.760 359825.300 953 25.880 3117 26.160 632 26.620 461 26.900 426 27.540 58428.920 312 31.400 546 31.780 247 33.320 270 38.440 357 39.140 307 39.660103

Above powder X-ray diffraction analysis data were measured by the sameconditions as Example 23(2).

(5) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form C)

Crude crystals (2 g) prepared by the above procedure (2) was dissolvedunder heating into tetrahydrofuran (20 mL). After confirming completedissolution, the solution was cooled to −30° C. Heptane (30 mL) wasdropwise added to the tetrahydrofuran solution, followed by stirring at−30° C. for one hour. The yielded colorless crystals were collected byfiltration, washed with heptane (5 mL) and dried in vacuum at roomtemperature for 15 hours to obtain 1.90 g of the above-identifiedproduct (monotetrahydrofuran solvate, the crystal form C) as colorlessfine granules.

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 5.940 1209 7.680 7150 11.420 1480 13.1802032 14.240 1859 14.840 623 15.460 2629 16.580 2244 16.800 4076 17.960706 18.640 2479 20.340 296 21.260 699 21.680 839 22.220 642 23.040 251524.000 1355 25.220 467 26.500 850 27.160 840 27.640 1078 28.780 38930.940 283 34.200 267

Above powder X-ray diffraction analysis data were measured by the sameconditions as Example 23(2).

(6) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form D)

Spiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (515 mg)and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (583 mg) were dissolvedinto dimethyl sulfoxide (2.6 mL), followed by dropwise addition ofdimethylbenzylamine (0.33 mL). The temperature of the resultant mixturewas raised up to 50° C., and the mixture was stirred for one hour. Thereaction mixture was cooled to room temperature, and acetonitrile/water(1:2) mixture solution (7.8 mL) was dropwise added. At the time when 0.2mL of the mixture solution was added, seed crystal was added. Theresultant mixture was stirred at room temperature for 6 hours. Theyielded colorless crystals were collected by filtration, washed withacetonitrile/water (1:1) and dried in vacuum at room temperature for 15hours to obtain the above-identified compound (793 mg) as crudecolorless crystals. Crude crystals (26 g) prepared by the repetition ofthe above procedure were suspended in water-saturated isopropyl acetate(143 mL). The mixture was seeded with seed crystal and stirred at roomtemperature for 18 hours. The yielded crystals were collected byfiltration, washed with isopropyl acetate (20 mL) and dried in vacuum at30° C. for 15 hours to obtain the above-identified compound in thecrystal form D (25.2 g) as colorless crystals (melting point; 206° C.measured without correction by the use of Melting Point B-545distributed by Buchi Company).

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 9.680 337 10.260 1796 11.480 1921 11.8002608 12.580 2119 13.160 5843 13.900 1413 15.440 4091 15.660 4780 16.5201853 17.520 298 19.320 1748 20.220 4858 20.660 2115 21.020 1063 21.480493 21.820 856 22.280 947 22.700 2126 23.140 13619 23.640 502 24.4603174 25.400 1919 26.060 1306 26.580 860 26.960 337 28.040 1036 28.620188 29.080 852 30.160 328 30.880 617 31.820 728 37.460 315

Above powder X-ray diffraction analysis data were measured by the sameconditions as Example 23(2).

(7) Preparation of3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide(Crystal Form B)—an alternative method for preparation

Crude crystals (26 g) prepared by the above procedure (6) was suspendedin acetonitrile (260 mL). The mixture was seeded with the seed crystalprepared by the above procedure (4) and stirred at room temperature for24 hours. The yielded crystals were collected by filtration, washed withacetonitrile (50 mL) and dried in vacuum at 30° C. for 15 hours toobtain the above-identified product in the crystal form B (25.5 g).

Compounds of Example 24 to 39 were obtained in the similar manner asExample 22 by replacing phenyl N-(4-benzoylphenyl)carbamate used inExample 22 by the corresponding materials, respectively.

Example 24 N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 178-180° C.

Example 253-Oxo-N-(3-phenyl-5-isoxazolyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 239-242° C.

Example 263-Oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 246-248° C.

Example 273-Oxo-N-(5-phenyl-2-pyrimidinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 211-214° C.

Example 283-Oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 251-254° C.

Example 29 3-Oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 160-165° C.

Example 30N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 255-258° C.

Example 313-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 253-257° C.

Example 32N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 122-125° C.

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 4.96 5335 9.94 2512 13.82 1020 14.56 55514.64 565 14.94 1705 16.14 1067 16.66 2260 17.12 1668 17.60 1420 17.92590 19.40 447 19.80 788 19.94 627 20.42 1057 21.00 963 21.80 1698 22.062397 22.36 1235 23.96 555 24.16 632 24.32 402 25.08 1603 25.38 538 26.82647 27.06 1345 27.84 1073 28.80 465 28.86 493 29.42 752 30.30 1015 30.74850 34.16 422 38.12 918 42.36 625 43.88 528

Above powder X-ray diffraction analysis data were measured by RINT2100Ultima+ System(2 KW) (manufactured by Rigaku International Corporation)and analysis methods were as follows:

X-ray radiation source: Cu,

tube voltage: 40 kV,

tube current: 30 mA,

monochromater: automatic monochromater,

monoreceiving slit: 0.15 mm,

goniometer: Horizontal goniometer I,

scan step: 0.02 deg.,

scan speed: 2.00 deg./min.,

divergence slit(DS): 1 deg.,

scattering slit: 1 deg.,

receiving slit (RS): 0.15 mm,

measured temperature: ambient temperature.

Example 333-Oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 190-192° C.

Example 34N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 126-128° C.

Example 35N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 193° C.

Example 363-Oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 239-241° C.

Example 37N-{1-[3-(2-hydroxyethyl)phenyl]-4-imidazolyl}-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 99-100° C.

Example 38N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 221-223° C.

Example 39N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

melting point 208-210° C.

Example 40 Preparation of6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

A mixture of 6-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (64 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg)and triethylamine (174 μL) in chloroform (5 mL) was stirred at 80° C.for 2 hours. The reaction mixture was poured into water and extractedwith chloroform (20 mL). The organic layer was washed with saturatedsaline solution (20 mL), then dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized fromethyl ether-hexane to give the subject compound (101 mg) as colorlesscrystals (melting point 222-224° C.).

Example 41 Preparation of6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[iso-benzofuran-1(3H),4′-piperidine]-1′-carboxamide

The subject compound was obtained in the similar manner as Example 40 byreplacing phenyl N-(5-phenyl-2-pyrazinyl)carbamate used in Example 40 byphenyl N-(5-phenyl-2-pyrimidinyl)carbamate.

melting point 176-178° C.

Example 42 Preparation of5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzo-furan-1(3H),4′-piperidine]-1′-carboxamide

A mixture of 5-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (64 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg)and triethylamine (174 μL) in chloroform (5 mL) was stirred at 80° C.for 2 hours. The reaction mixture was poured into water and extractedwith chloroform (20 mL). The organic layer was washed with saturatedsaline solution (20 mL), then dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by column chromatography onsilica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized fromethyl ether-hexane to give the subject compound (100 mg) as colorlesscrystals (melting point 236-238° C.).

Example 43 Preparation of5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[iso-benzofuran-1(3H),4′-piperidine]-1′-carboxamide

The subject compound was obtained in the similar manner as Example 42 byreplacing phenyl N-(5-phenyl-2-pyrazinyl)carbamate used in Example 42 byphenyl N-(5-phenyl-2-pyrimidinyl)carbamate.

melting point 255-257° C.

Example 44 Preparation ofN-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide

Spiro[1H-2-benzopyran-1,4′-piperidine]-3(4H)-one hydrochloride (50.6 mg)and phenyl N-(4-benzoylphenyl)carbamate (63.4 mg) were suspended indimethyl sulfoxide (1.0 mL) and the suspension was vigorously stirredtogether with aqueous 10M sodium hydroxide (30 μL) for 5 minutes. Thereaction mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with saturated saline solution,then dried over anhydrous Na₂SO₄ and concentrated. The residue wascrystallized from methanol-diisopropyl ether to give the subjectcompound (68.0 mg) as colorless crystals (melting point 138-146° C.).

Compounds of Example 45 and 46 were obtained in the similar manner asExample 44 by replacing phenyl N-(4-benzoylphenyl)carbamate used inExample 44 by the corresponding materials, respectively.

Example 453,4-Dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide

melting point 221° C.

Example 46N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide

melting point 128-131° C.

Example 47 Preparation oftrans-N-(4-benzoylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

(1) Preparation of spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′,4-dione

A solution of 2-bromobenzoic acid (4.77 g) in anhydrous tetrahydrofuran(100 mL) was cooled to −78° C. under an atmosphere of nitrogen, to whichn-butyllithium (1.53M solution in hexane, 31 mL) was dropwise addedwhile being kept the internal temperature below −55° C. After beingstirred for 1 hour, a solution of 1,4-cyclohexanedione monoethyleneketal (5.18 g) in anhydrous tetrahydrofuran (10 mL) was added dropwiseto the mixture while being kept the internal temperature below −67° C.After the temperature was raised to room temperature, the reactionsolution was partitioned between water (150 mL) and hexane (100 mL). Theaqueous layer was acidified with concentrated hydrochloric acid andrefluxed together with acetone (10 mL) for 2 hours. After cooling, thusobtained mixture was neutralized with potassium carbonate and extractedwith ethyl acetate. The organic layer was washed with saturated salinesolution, then dried over anhydrous Na₂SO₄ and evaporated. The residuewas crystallized from ethyl acetate-hexane to give the subject compound(2.42 g).

(2) Preparation of4-methylenespiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3-one

A suspension of methyltriphenylphosphonium bromide (715 mg) in anhydroustetrahydrofuran (7.0 mL) was cooled to 0° C. under an atmosphere ofnitrogen, to which n-butyllithium (1.53M solution in hexane, 1.3 mL) wasadded, stirred at that temperature for 20 minutes and then cooled to−78° C. A solution ofspiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′,4-dione (216 mg) inanhydrous tetrahydrofuran (3 mL) was added to the reaction mixture andthe temperature was raised to 0° C. After stirring for 20 minutes,aqueous ammonium chloride was added to thus obtained mixture and theresulting crude product was extracted with ethyl acetate. The organiclayer was washed with saturated saline solution, then dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=4/1) to give thesubject compound (196 mg).

(3) Preparation of4-hydroxymethylspiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′-one

A solution of4-methylenespiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3-one (196 mg) inanhydrous tetrahydrofuran (5.0 mL) was cooled to 0° C., to whichborane-dimethyl sulfide complex (2M tetrahydrofuran solution, 690 μL)was added and the mixture was stirred at that temperature for 1.5 hours,then additional 20 minutes together with aqueous 2M sodium hydroxide(5.0 mL) and aqueous 30% hydroperoxide (5.0 mL). The reaction mixturewas diluted with water, extracted with ethyl acetate, washed withsaturated saline solution, then dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=2/1) to give the subject compound (190 mg) asdiastereomers.

(4) Preparation oftrans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxylic acid

A mixture of4-hydroxymethylspiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3′-one (190mg), chloroform (2.0 mL), acetonitrile (2.0 mL) and sodium phosphatebuffer (pH6.5, 2.0 mL) was cooled to 0° C., to which sodium periodate(612 mg) and ruthenium(III) chloride n-hydrate (10 mg) were added andthe mixture was stirred for 30 minutes. The reaction mixture was stirredtogether with 1N hydrochloric acid (2.0 mL) for 30 minutes andpartitioned between water (50 mL) and ethyl acetate (50 mL). The organiclayer was washed with saturated saline solution, dried over anhydrousNa₂SO₄ and then concentrated. The residue was purified by columnchromatography on silica gel (chloroform/methanol=100/1) to give thesubject compound (98.6 mg).

(5) Preparation oftrans-N-(4-benzoylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

To a solution oftrans-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxylic acid(24.6 mg) in pyridine (500 μL), 4-aminobenzophenone (19.8 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (57.5 mg)were added and the mixture was stirred at 50° C. for 2 hours. Thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with aqueous potassium hydrogen sulfate,aqueous sodium hydrogen carbonate, and saturated saline solution andthen dried over anhydrous Na₂SO₄ and evaporated. The residue wascrystallized from ethyl acetate-hexane to give the subject compound(31.2 mg) as colorless crystals (melting point 194° C.).

Compounds of Example 48 to 56 were obtained in the similar manner asExample 47-(5) by replacing 4-aminobenzophenone used in Example 47-(5)by the corresponding materials, respectively.

Example 48Trans-3′-oxo-N-(5-phenyl-2-pyrazinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 223° C.

Example 49Trans-3′-oxo-N-(1-phenyl-4-imidazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 264° C.

Example 50Trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 184° C.

Example 51Trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 294° C.

Example 52Trans-3′-oxo-N-(5-phenyl-3-pyrazolyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 238° C.

Example 53Trans-N-[1-(2-fluorophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 258° C.

Example 54Trans-N-1(4-acetyl-3-trifluoromethylphenyl)-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 274-275° C.

Example 55Trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point>300° C.

Example 56Trans-N-[1-(3-cyanophenyl)-4-imidazolyl]-3′-oxospiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide

melting point 268-270° C.

Example 57 Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

(1) Preparation ofdispiro[4-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one

A solution of N-methyl-2-pyridinecarboxamide (9.53 g) in anhydroustetrahydrofuran (400 mL) was cooled to −78° C. under an atmosphere ofnitrogen, to which n-butyllithium (1.54M solution in hexane, 100 mL) wasdropwise added. After being stirred for 1.5 hours at the sometemperature, a solution of 1,4-cyclohexanedione monoethylene ketal(10.93 g) in anhydrous tetrahydrofuran (100 mL) was added dropwise tothe mixture. After the temperature was raised to room temperature, thereaction mixture was partitioned between water (300 mL) and ethyl ether(100 mL). The aqueous layer was acidified with 2N hydrochloric acid,stirred for 30 minutes, neutralized with potassium carbonate and thenleft overnight. The resulting precipitate was collected by filtrationand dried to give the subject compound (6.84 g).

(2) Preparation ofspiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

A mixture ofdispiro[4-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one(6.8 g), 2N hydrochloric acid (20 mL) and acetone (5 mL) was heatedunder reflux for 13 hours. After cooling, the mixture was neutralizedwith potassium carbonate and stirred together with isopropyl ether (5mL) for 3 hours. The resulting precipitate was collected by filtration,washed with water and isopropyl ether and then dried to give the subjectcompound (3.39 g).

(3) Preparation ofcis-4′-hydroxyspiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

Spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione (5.7 g) wasdissolved in tetrahydrofuran (50 mL) and water (10 mL) and cooled to 0°C. The solution was stirred together with sodium borohydride (993 mg)for 20 minutes, acidified with 10% sulfuric acid, adjusted to pH7.4 withsaturated sodium hydrogen carbonate aqueous solution and extracted withchloroform-ethanol and chloroform-tetrahydrofuran. The organic layer wasdried over anhydrous Na₂SO₄ and concentrated. The residue wascrystallized from ethyl acetate-isopropyl ether to give the subjectcompound (2.02 g).

(4) Preparation oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

To a solution ofcis-4′-hydroxyspiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one (2.02g) in anhydrous tetrahydrofuran (60 mL), triethylamine (3.08 mL) wasadded and cooled to 0° C. Methanesulfonyl chloride (1.3 mL) was addeddropwise to the mixture and stirred at that temperature for 1 hour. Thereaction mixture was diluted with water and extracted with chloroform.The organic layer was dried over anhydrous Na₂SO₄ and evaporated. Theresidue was crystallized from ethyl acetate-isopropyl ether to givemesylate (2.47 g). Thus obtained mesylate was dissolved indimethylformamide (25 mL) and stirred together with tetraethylammoniumcyanide (3.25 g) at 100° C. for 3 hours. After cooling, the reactionmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and saturated saline solution, driedover anhydrous Na₂SO₄ and then concentrated. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=2/3) to givethe subject compound (1.0 g).

(5) Preparation oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid

A solution oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(1.0 g) in 30% sulfuric acid was heated under reflux for 11 hours. Aftercooling, the reaction mixture was diluted with water and adjusted to pH6with potassium carbonate. The resulting precipitate was collected byfiltration, washed with water and air-dried to give the subject compound(974 mg).

(6) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

To a solution oftrans-3-oxospiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (66 mg) in pyridine (1 mL), 4-aminobenzophenone (52.6 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (153 mg)were added and the mixture was stirred at 40° C. for 2 hours. Thereaction mixture was concentrated and the residue was partitionedbetween water and ethyl acetate. The organic layer was washed withsaturated saline solution, dried over anhydrous Na₂SO₄ and thenconcentrated. The residue was crystallized from ethyl acetate-hexane togive the subject compound (94.4 mg) as colorless crystals (melting point237° C.).

Compounds of Example 58 to 60 were obtained in the similar manner asExample 57-(6) by replacing 4-aminobenzophenone used in Example 57-(6)by the corresponding materials, respectively.

Example 58Trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 203° C.

Example 59Trans-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 217° C.

Example 60Trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 237° C.

Example 61 Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

(1) Preparation ofdispiro[5-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one

2,2,6,6-Tetramethylpiperidine (41.1 mL) was dissolved in anhydroustetrahydrofuran (400 mL) and cooled to −50° C., to which n-butyllithium(1.50M solution in hexane, 217 mL) and nicotinic acid (10.0 g) wereadded successively. After being stirred at −50° C. for 1 hour, asolution of 1,4-cyclohexanedione monoethylene ketal (13.9 g) inanhydrous tetrahydrofuran (25 mL) was added and then the mixture wasstirred at −50° C. for 1 hour. After the temperature was raised to roomtemperature, the reaction mixture was poured into water (800 mL) andextracted with hexane-ether (1:1, 500 mL). The aqueous layer wasadjusted to pH3 with 6N hydrochloric acid and stirred at roomtemperature for 2 hours. The resulting precipitate was collected byfiltration and washed with water. Thus obtained solid was dissolved inchloroform (300 mL), washed with saturated sodium bicarbonate aqueoussolution (150 mL), dried and then concentrated. The residue wasrecrystallized from ethyl acetate-hexane to give the subject compound(4.29 g).

(2) Preparation ofspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

Dispiro[5-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one(4.29 g) and p-toluenesulfonic acid monohydrate (3.74 g) were dissolvedin acetone (80 mL) and water (8 mL) and the solution was heated underref lux for 3 hours. After cooling, acetone was evaporated off andchloroform (100 mL) was added to the residue. The mixture was washedwith saturated sodium bicarbonate aqueous solution (50 mL×2), dried overanhydrous Na₂SO₄ and then evaporated. The resulting crystals wererecrystallized from ethyl acetate-hexane to give the subject compound(2.68 g).

(3) Preparation ofcis-4′-hydroxyspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

A suspension ofspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione (167 mg) intetrahydrofuran-water (10:1, 4 mL) was cooled to 0° C. and stirredtogether with sodium borohydride (32 mg) at 0° C. for 30 minutes. Thereaction mixture was poured into water (5 mL), stirred at roomtemperature for 30 minutes and then extracted with chloroform (20 mL×3).The extract was dried over anhydrous Na₂SO₄ and concentrated. Theresidue was recrystallized from ethyl acetate-hexane to give the subjectcompound (77.7 mg).

(4) Preparation of trans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

A solution ofcis-4′-hydroxyspiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one (1.31g) and triethylamine (1.17 mL) in anhydrous tetrahydrofuran (20 mL) wascooled to 0° C. and stirred together with methanesulfonyl chloride(0.555 mL) at 0° C. for 1 hour. The reaction mixture was poured intowater (50 mL), extracted with ethyl acetate (100 mL×2), dried overanhydrous Na₂SO₄ and concentrated to give crude mesylate (1.87 g). Themesylate was dissolved in anhydrous dimethylformamide (30 mL) andstirred together with triethylammonium cyanide (2.98 g) at 100° C. for 5hours. The reaction mixture was poured into water (100 mL) and extractedwith ether (150 mL×3), and ether-ethyl acetate (2:1, 200 mL). Thecombined extracts were dried over anhydrous Na₂SO₄ and concentrated. Theresulting oily residue was purified by column chromatography on silicagel (hexane/ethyl acetate/methanol=2/1/0 to 1/1/0 to 30/30/1) and theobtained solid was recrystallized from ethyl acetate-hexane to give thesubject compound (631 mg).

(5) Preparation of trans-3-oxospiro[5-azaisobenzofuran -1(3H),1′-cyclohexane]-4′-carboxylic acid

A mixture oftrans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(100 mg), water (0.7 mL) and concentrated sulfuric acid (0.3 mL) wasrefluxed for 11 hours. The reaction mixture was cooled to roomtemperature and adjusted to pH4 with aqueous 4N sodium hydroxide. Theresulting precipitate was collected by filtration, washed successivelywith water, ethanol and diisopropyl ether and then dried to give thesubject compound (78 mg).

¹H-NMR (200 MHz, DMSO-d₆, δ ppm): 1.63-1.87 (2H, m), 1.88-2.20 (6H, m),2.70 (1H, m), 7.76 (1H, dd, J=5.2, 1.1 Hz), 8.86 (1H, d, J=5.2 Hz), 9.06(1H, d, J=1.1 Hz).

(6) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

A solution oftrans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (20 mg) and 4-aminobenzophenone (16 mg) in anhydrous pyridine (0.5mL) was stirred together with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20 mg) at60° C. for 2 hours. The reaction mixture was poured into water (10 mL)and extracted with ethyl acetate (30 mL ×2). The combined organic layerswere dried over anhydrous Na₂SO₄ and concentrated. The resulting oilyresidue was purified by column chromatography on silica gel(hexane/ethyl acetate=1/1 to 1/2) and the obtained solid wasrecrystallized from ethyl acetate-hexane to give the subject compound(10 mg) as colorless crystals (melting point 256-257° C.).

Example 62 Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

(1) Preparation ofdispiro[6-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one

2,2,6,6-Tetramethylpiperidine (50 mL) was dissolved in anhydroustetrahydrofuran (500 mL) and the solution was cooled to −50° C., towhich n-butyllithium (1.50M solution in hexane, 270.7 mL) andisonicotinic acid (12.5 g) were added successively. The reaction mixturewas stirred at −50° C. for 10 minutes and the temperature was raised to25° C. over 30 minutes. The reaction mixture was further stirred at 25°C. for 10 minutes and then cooled to −65° C. 1,4-Cyclohexanedionemonoethylene ketal (19 g) was added and the reaction mixture was stirredat −65° C. for 10 minutes. The temperature of the reaction mixture wasraised to −15° C. over 1 hour, then to 0° C. over 30 minutes. Then themixture was poured into water (300 mL), from which the aqueous layer wasseparated. The organic layer was extracted with aqueous 2N sodiumhydroxide. The combined aqueous layers were adjusted to pH3 withconcentrated hydrochloric acid and extracted with ethyl acetate (500mL). The organic layer was washed with saturated aqueous sodiumbicarbonate (200 mL), and saturated saline solution, then dried overanhydrous MgSO₄ and concentrated. The residue was purified by columnchromatography on silica gel (hexane/ethyl acetate=1/0 to 4/1 to 3/2)and recrystallized from ethyl acetate-hexane to give the subjectcompound (7.20 g).

(2) Preparation ofspiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

Dispiro[6-azaisobenzofuran-1(3H),1′-cyclohexane-4′,2″-1″,3″-dioxolane]-3-one(7.20 g) and p-toluenesulfonic acid monohydrate (5.80 g) were dissolvedin acetone (150 mL) and water (15 mL) and the solution was heated underreflux for 5.5 hours. After cooling, acetone was evaporated off and theresidue was extracted with ethyl acetate (100 mL×3). The combinedorganic layers were washed with saturated saline solution (50 mL), driedover anhydrous MgSO₄ and then evaporated. The resulting crystals wererecrystallized from ethyl acetate-diisopropyl ether to give the subjectcompound (1.96 g).

(3) Preparation ofcis-4′-hydroxyspiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

A solution of spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione(1.0 g) in ethanol (100 mL) was cooled to 0° C. and stirred togetherwith sodium borohydride (174 mg) at 0° C. for 1 hour. The reactionmixture was adjusted to pH4 with 10% sulfuric acid, rendered basic withaqueous saturated sodium bicarbonate and then extracted with chloroform(200 mL×2). The extract was dried over anhydrous MgSO₄ and concentrated.The residue was recrystallized from ethyl acetate-hexane to give thesubject compound (954.5 mg).

(4) Preparation oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

A solution ofcis-4′-hydroxyspiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one (954mg) and triethylamine (0.91 mL) in dimethylformamide (10 mL) was cooledto 0° C. and stirred together with methanesulfonyl chloride (0.40 mL) at0° C. for 1 hour. The reaction mixture was diluted with ethyl acetate(100 mL), washed with aqueous saturated sodium bicarbonate (50 mL×2),and saturated saline solution (50 mL), then dried over anhydrous MgSO₄and concentrated. The residue was recrystallized from ethylacetate-diisopropyl ether to give mesylate (995 mg). This mesylate wasdissolved in anhydrous dimethylformamide (30 mL) and stirred togetherwith triethylammonium cyanide (1.57 g) at 100° C. for 1.5 hours. Thereaction mixture was diluted with ethyl acetate (200 mL) and washedsuccessively with water (200 mL), aqueous saturated sodium bicarbonate(200 mL), and saturated saline solution (100 mL). The organic layer wasdried over anhydrous MgSO₄ and concentrated. The residue wasrecrystallized from ethyl acetate-diisopropyl ether to give the subjectcompound (447 mg).

(5) Preparation oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid

A mixture oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(445 mg), water (3.5 mL) and concentrated sulfuric acid (1.5 mL) wasrefluxed for 6 hours. The reaction mixture was cooled to roomtemperature and adjusted to pH8 with aqueous 5N sodium hydroxide, thento pH4 with concentrated hydrochloric acid. The resulting crystals werecollected by filtration, washed with water and dried to give the subjectcompound (416 mg) as colorless crystals (melting point 222-223° C.).

¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 1.7-2.2 (6H, m), 2.65-2.75 (1H, m),7.83 (1H, dd, J=1.2 Hz, 4.9 Hz), 8.86 (1H, d, J=4.9 Hz), 9.05 (1H, d,J=1.2 Hz), 12.3 (1H, brs).

(6) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

A solution oftrans-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (50 mg) and 4-aminobenzophenone (51.6 mg) in anhydrous pyridine (1mL) was stirred together with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48.7 mg) at60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate(20 mL) and washed successively with water (20 mL), 10% citric acidaqueous solution (20 mL×2), aqueous saturated sodium bicarbonate, andsaturated saline solution. The organic layer was dried over anhydrousMgSO₄ and concentrated. The resulting oily residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=3/2 to 1/4)and the obtained solid was recrystallized from ethyl acetate-hexane togive the subject compound (62.7 mg) as colorless crystals (melting point147-149° C.).

Example 63 Preparation ofN-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

(1) Preparation of 2-amino-5-(4-hydroxyphenyl)pyrazine

To a solution of 2-amino-5-bromopyrazine (366 mg) in dimethoxyethane (20mL) was added 4-hydroxyphenylboronic acid (320 mL), 1.5N sodiumcarbonate aqueous solution (2.5 mL) and tetrakis (triphenylphosphine)palladium (0) (54 mg). The mixture was stirred at 80° C. for 3 hours. Tothe reaction mixture was added water (20 mL) and the whole was extractedwith ethyl acetate (50 mL×3). The extract was washed with saturatedsaline solution, then dried over anhydrous Na₂SO₄. The removal of thesolvent provided crystal residue, which was washed with diethyl ether(10 mL) to give the subject compound (305 mg).

(2) Preparation of phenyl N-[5-(4-hydroxyphenyl)-2-pyrazinyl]carbamate

To solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283 mg) in pyridine(20 mL) was added under ice-cooling phenyl chloroformate (199 μL) andthe mixture was stirred for 1 hour. The reaction mixture was poured intowater (30 mL) and extracted with ethyl acetate (20 mL×3). The organiclayer was washed with saturated saline solution and then dried overanhydrous Na₂SO₄. The concentration of the solvent left a crystalresidue, which was washed with diethyl ether (10 mL) to give the subjectcompound (314 mg).

(3) Preparation ofN-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (96 mg), phenylN-5-[(4-hydroxyphenyl)-2-pyrazinyl]carbamate (128 mg) and triethylamine(279 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours.

The reaction mixture was poured into water and extracted with chloroform(20 mL). The organic layer was washed with saturated saline solution (20mL) and then dried over anhydrous Na₂SO₄.

The concentration of the solvent left a residue, which was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2)followed by recrystallization from ethyl ether-hexane to give thesubject compound (114 mg) as colorless crystals (melting point 263-265°C.).

Example 64 Preparation ofN-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

(1) Preparation of 2-amino-5-(3-methoxyphenyl)pyrazine

To a solution of 2-amino-5-bromopyrazine (642 mg) in dimethoxyethane (40mL) was added 3-methoxyphenylboronic acid (560 mg), 1.5N aqueous sodiumcarbonate solution (4 mL) and tetrakis(triphenylphosphine) palladium (0)(86 mg). The mixture was stirred at 80° C. for 6 hours. To the reactionmixture was added water (20 mL) and the whole was extracted with ethylacetate (50 mL×3). The extract was washed with saturated saline solutionand then dried over anhydrous Na₂SO₄. The concentration of the solventleft a crystal residue, which was washed with ethyl ether (10 mL) togive the subject compound (760 mg).

(2) Preparation of 2-amino-5-(3-hydroxyphenyl)pyrazine

2-amino-5-(3-methoxyphenyl)pyrazine (566 mg) was dissolved in methylenechloride (10 mL). To this mixture was added under ice-cooling borontribromide (530 μL) and the whole was stirred at room temperature for 14hours. To the reaction mixture was added 1N aqueous sodium hydroxide.The whole was extracted with ethyl acetate (30 mL×2). The organic layerwas washed with saturated saline solution and then dried over anhydrousNa₂SO₄. The concentration of the solvent provides the subject compound(94 mg) as a yellow solid.

(3) Preparation of Phenyl N-[5-(3-hydroxyphenyl)-2-pyrazinyl]carbamate

To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg) in pyridine(10 mL) was added under ice-cooling phenyl chloroformate (63 μL). Themixture was stirred for 1 hour and then poured into water (30 mL) andextracted with ethyl acetate (20 mL×3). The extract was washed withsaturated saline solution and then dried over anhydrous Na₂SO₄. Theconcentration of the solvent left a crystal residue, which was washedwith ethyl ether (10 mL) to give the subject compound (51 mg).

(4) Preparation ofN-[5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

A mixture of spiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (40 mg), phenylN-[5-(3-hydroxyphenyl)-2-pyrazinyl]carbamate (51 mg) and triethylamine(119 μL) in chloroform (5 mL) was stirred at 80° C. for 2 hours. Thereaction mixture was poured into water and extracted with chloroform (20mL). The organic layer was washed with saturated saline solution (20 mL)and then dried over anhydrous Na₂SO₄. The concentration of the solventleft a residue, which was purified by column chromatography on silicagel (hexane/ethyl acetate=4/1 to 1/2) followed by recrystallization fromethyl ether-hexane to give the subject compound (24 mg) as colorlesscrystals (melting point 257-259° C.).

Example 65 Preparation of4-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1-carboxamide

A mixture of 4-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60°C. for 3 hours. The concentration of the reaction mixture left aresidue, which was purified by column chromatography on silica gel(hexane/ethyl acetate/methanol=1/1/0˜8/8/1˜6/6/1) followed byrecrystallization from ethyl acetate-hexane to give the subject compound(190 mg) as colorless crystals (melting point 247-249° C.).

Example 66 Preparation of7-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

A mixture of 7-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (150 mg), phenyl N-(5-phenyl-2-pyrimidinyl)carbamate (170mg) and triethylamine (0.24 mL) in chloroform (2 mL) was stirred at 60°C. for 2 hours. The reaction mixture was diluted with ethyl acetate. Thewhole was washed with 10% citric acid aqueous solution, saturatedaqueous sodium bicarbonate and saturated saline solution and then driedover anhydrous Na₂SO₄. The concentration of the reaction mixture left aresidue, which was recrystallized from ethyl acetate to give the subjectcompound (202 mg) as colorless crystals (melting point 244-246° C.).

Example 67 Preparation of6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

(1) Preparation of 2-(4-ethylphenyl)-4,4-dimethyl-2-oxazoline

To a solution of 4-ethylbenzoic acid (3.80 g) in anhydrous acetonitrile(100 mL) was added under a nitrogen atmosphere, triphenylphosphine (20g), 2-amino-2-methyl-1-propanol (2.74 mL) and triethylamine (28.2 mL).The mixture was cooled on an ice bath and then tetrachloromethane (5.36mL) was added. The reaction mixture was allowed to stand at roomtemperature and stirred for 18 hours. To the reaction mixture was addedethyl acetate and hexane and the precipitate was removed by filtration.The concentration of the filtrate left a residue, which was purified bycolumn chromatography on silica gel (hexane/ethyl acetate/=9/1/ to 6/1)to give the subject compound (1.15 g).

(2) Preparation of1′-benzyl-6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride

Under a nitrogen atmosphere, a solution of2-(4-ethylphenyl)-4,4-dimethyl-2-oxazoline (1.15 g) in anhydroustetrahydrofuran (100 mL) was cooled to −78° C. To this solution wasadded 1.5 M butyl lithium hexane solution (4.53 mL). After being stirredfor 1 hour, 1-benzyl-4-piperidone (1.05 mL) was added dropwise. Afterthe reaction temperature was allowed to rise up to room temperature, 2Nhydrochloric acid was added to the reaction mixture to make the mixtureacidic. The whole was refluxed for 2 hours. After cooling, sodiumhydroxide aqueous solution was added to make the reaction mixture basic.The mixture was extracted with ethyl ether. The organic layer was washedwith saturated saline solution and then dried over anhydrous Na₂SO₄. Theconcentration of the organic solvent left a residue, which was purifiedby column chromatography on silica gel (hexane/ethyl acetate/=3/2) togive the subject compound (409 mg).

(3) Preparation of 6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride

1′-benzyl-6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (400 mg) was dissolved in methanol (10 mL) and 10%palladium carbon was added. The mixture was stirred under a hydrogenatmosphere for 1.5 hours. After the palladium carbon was removed byfiltration, the filtrate was concentrated to give a residue, which wassubjected to crystallization with methanol-ethyl ether to give thesubject compound (222 mg).

(4) Preparation of6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

To a suspension of 6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (53 mg) and phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58mg) in dimethyl sulfoxide (1 mL) was added 10 M sodium hydroxide aqueoussolution (0.02 mL). The mixture was vigorously stirred for 5 minutesfollowed by partition between water and ethyl acetate. The organic layerwas separated and then washed with saturated saline solution and thendried over anhydrous Na₂SO₄. The concentration of the organic solventleft a residue, which was subjected to the crystallization from ethylacetate to give the subject compound (46 mg) as crystals (melting point176-178° C.).

Example 68 Preparation of6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

(1) Preparation of 2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline

To a solution of 2-amino-2-methyl-1-propanol (14.4 g) and triethylamine(23 mL) in dried THF (200 mL) was added dropwise under ice-cooling asolution of 4-methoxybenzoyl chloride (25 g) in dried THF (20 mL). Themixture was stirred at room temperature for 1 hour and then water (200mL) was added. The reaction mixture was extracted with ethyl acetate(100 mL) twice. The organic layer was washed with saturated salinesolution and then dried over anhydrous Na₂SO₄. The concentration of theorganic solvent provided the subject compound (29.5 g) as a white solid.Thionyl chloride (25 mL) was added to the above white solid compound,and the reaction was carried out at room temperature for one hour. Thereaction mixture was made alkaline by the addition of 5N sodiumhydroxide aqueous solution and was extracted twice each with ethylacetate (100 mL). The combined organic layer was washed with saturatedsodium chloride aqueous solution and dried with anhydrous sodiumsulfate. The solvent was evaporated off to give the above-identifiedcompound (22 g) as colorless oil.

(2) Preparation of1′-benzyl-6-methoxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-one

Under a nitrogen atmosphere, to a solution of2-(4-methoxyphenyl)-4,4-dimethyl-2-oxazoline (7.9 g) in anhydroustoluene (100 mL) was added dropwise under ice-cooling 1.5M butyl lithiumhexane solution (28 mL). After being stirred for 3 hours at the sametemperature, 1-benzyl-4-piperidone (8 g) in anhydrous toluene (20 mL)was added dropwise. After the reaction mixture was stirred at roomtemperature for 14 hours, a saturated ammonium chloride aqueous solution(50 mL) was added. The mixture was extracted with ethyl acetate (100 mL)twice. The organic layer was washed with saturated saline solution andthen dried over anhydrous Na₂SO₄. The concentration of the organicsolvent provided the compound (8.3 g) as a white solid. This compoundwas dissolved in methanol (50 mL) and concentrated sulfuric acid (4 mL)was added. The mixture was stirred at room temperature for 1 hour. Tothe reaction mixture was added 1N sodium hydroxide aqueous solution tomake the reaction mixture basic. The mixture was extracted with ethylacetate (100 mL) twice. The organic layer was washed with saturatedsaline solution and then dried over anhydrous Na₂SO₄. The concentrationof the organic solvent provided the subject compound (6.6 g) as a yellowsolid.

(3) Preparation of6-hydroxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride

1′-benzyl-6-methoxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-one (1.8g) was dissolved in methylene chloride (20 mL). To this solution wasadded under ice-cooling boron tribromide (1.3 mL). After the reactionmixture was stirred at room temperature for 14 hours, 1N sodiumhydroxide aqueous solution was added. The mixture was extracted withethyl acetate (30 mL) twice. The organic layer was washed with saturatedsaline solution and then dried over anhydrous Na₂SO₄. The concentrationof the organic solvent provided the compound (1.2 g) as a yellow solid,which was dissolved in methanol (30 mL). To this solution was added 4Nhydrogen chloride-ethyl acetate (5 mL), 20% palladium hydroxide-carbon(300 mg). The mixture was stirred under a hydrogen atmosphere for 14hours. After the catalyst was removed by filtration, the filtrate wasconcentrated to give the subject compound (891 mg) as a white solid.

(4) Preparation of6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide

A mixture of 6-hydroxyspiro[isobenzofuran-1(3H),4′-piperidine]-3-onehydrochloride (51 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (58 mg)and triethylamine (119 μL) in chloroform (5 mL) was stirred at 80° C.for 2 hours. The reaction mixture was poured into water, and thenextracted with chloroform (20 mL). The organic layer was washed withsaturated saline solution (20 mL) and then dried over anhydrous Na₂SO₄.The concentration of the organic solvent left a residue, which waspurified by column chromatography on silica gel (hexane/ethylacetate/=4/1 to 1/2) followed by the recrystallization from ethylether-hexane to give the subject compound (29 mg) as colorless crystals(melting point 206-208° C.).

The compounds from Example 69 to Example 79 were prepared, according tothe same preparation procedure described in Example 61 by using thecorresponding starting material in place of 4-aminobenzophenon used inthe Example 61.

Example 69trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide.

melting point 215-217° C.

Example 70trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 205-207° C.

Example 71trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxispiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 226-228° C.

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 11.14 970 14.62 1418 15.02 570 15.12 92015.56 895 16.22 475 17.10 1873 19.22 1698 20.06 3202 20.54 542 20.781013 21.00 1063 21.78 2405 23.24 5557 24.12 555 24.90 888 25.98 48726.30 500 27.52 2765 28.22 690 28.56 553 28.82 647 29.04 423 29.70 65330.54 1102 32.84 362 36.46 408

Above powder X-ray diffraction analysis data were measured by the sameconditions as Example 32.

Example 72trans-3-oxo-N-(4-phenyl-2-oxazolyl)spiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 273-275° C.

Example 73trans-N-[5-(2-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 213-215° C.

Example 74trans-N-[5-(3-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 145-147° C.

Example 75trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 157-159° C.

Example 76trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 153-155° C.

Example 77trans-N-[5-(3-fluoro-5-methoxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 218-220° C.

Example 78trans-N-[5-(2-fluoro-5-methylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 151-153° C.

Example 79trans-N-[4-(3-fluoromethoxylphenyl)-2-oxazolyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 214-217° C.

Example 80 Preparation oftrans-N-[5-(3-hydroxymethylphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

To a solution of 2-chloro-1,3-dimethylimidazolium chloride (613 mg) inchloroform (10 mL) was added pyridine (0.489 mL),trans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (300 mg) and 2-amino-5-bromopyrimidine (211 mg). The mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate.

The whole was washed with 10% citric acid aqueous solution, saturatedsodium bicarbonate aqueous solution, saturated saline solution and thendried over anhydrous Na₂SO₄. The concentration of the organic solventleft a residue, which was purified by column chromatography on silicagel (hexane/ethyl acetate=1/1 to 1/3 to 1/4 to 1/5) followed by thecrystallization from ethyl acetate to give the desired amide (210 mg).This amide was suspended in ethyleneglycol dimethyl ether (3.5 mL), andwater (0.5 mL), 3-hydroxymethylphenylboronic acid (95 mg), 2M sodiumcarbonate aqueous solution (0.31 mL) andtetrakistriphenylphosphinepalladium (30 mg) was added thereto.

The mixture was refluxed for 2 hours and then diluted with water. Thewhole was extracted with ethyl acetate and then dried over anhydrousNa₂SO₄. The concentration of the organic solvent left a residue, whichwas purified by column chromatography on silica gel (ethylacetate/methanol=1/0 to 30/1 to 20/1 to 15/1) to give the subjectcompound (151 mg) as light yellow crystals (melting point 207-209° C.).

Example 81 Preparation oftrans-N-[5-(3-hydroxyphenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

To a solution of 2-chloro-1,3-dimethylimidazolium chloride (622 mg) inchloroform (7 mL) was added pyridine (0.50 mL),trans-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (303 mg) and 2-amino-5-(3-benzyloxyphenyl)pyrimidine (340 mg). Themixture was stirred at room temperature overnight. The reaction mixturewas diluted with ethyl acetate. The whole was washed with 10% citricacid aqueous solution, saturated sodium bicarbonate aqueous solution,saturated saline solution and then dried over anhydrous Na₂SO₄. Theconcentration of the organic solvent left a residue, which was purifiedby column chromatography on silica gel (hexane/ethyl acetate=1/1 to 1/2to 1/4 to 1/5 to 1/6) followed by the crystallization from ethyl acetateto give the desired amide (210 mg). This amide was dissolved in methanol(5 mL) and tetrahydrofuran (5 mL), and 10% palladium-carbon (120 mg) wasadded. The mixture was stirred at room temperature under a hydrogenatmosphere overnight. The catalyst was removed by filtration. Thefiltrate was concentrated to give a residue, which was purified bycolumn chromatography on silica gel (chloroform/methanol=50/1 to 30/1)to give a solid compound. The solid compound was washed with ethanol andthen recrystallized from ethyl acetate to give the subject compound (95mg) as light yellow crystals (melting point 260-262° C.).

The compounds from Example 82 to Example 89 were prepared, according tothe same preparation procedure described in Example 62 by using thecorresponding starting material in place of 4-aminobenzophenon used inthe Example 62.

Example 82trans-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 189-191° C.

Example 83trans-N-[5-(3-fluoromethylphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 199-200° C.

Example 84trans-N-[5-(3-fluoromethoxyphenyl)-2-pyrimidinyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 198-200° C.

Example 85trans-3-oxo-N-(6-phenyl-1,2,4-triazin-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 272-275° C.

Example 86trans-N-[5-(2-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 239-240° C.

Example 87trans-N-[5-(3-difluoromethoxyphenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 183-185° C.

Example 88trans-N-[5-(3-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 182-184° C.

Example 89trans-N-[5-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 228-229° C.

Example 90 Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]4′-carboxamide

(1) Preparation of 3-cyano-2-hydroxypyridine

To malonaldehyde bisdimethylacetal (16.4 g) was added 0.5 N hydrochloricacid (40 mL). The mixture was stirred at 50° C. for 20 minutes and thencooled to room temperature. To the reaction mixture was addedtriethylamine (16 mL) followed by 2-cyanoacetoamide (9 g). The whole wasstirred at room temperature for 30 minutes and further heated at 60° C.for 90 minutes as well as 100° C. for 2 hours. After cooling, thereaction mixture was concentrated to give a residue, which wasrecrystallized from ethanol-ethyl ether to give the subject compound(7.49 g).

(2) Preparation of 2-bromo-3-cyanopyridine

Tetrabutylammonium bromide (35.4 g) and diphosphorus pentaoxide (15.58g) was suspended in toluene 100 mL). After the mixture was stirred at70° C. for 30 minutes, 3-cyano-2-hydroxypyridine (6.59 g) was addedthereto. The mixture was refluxed for 4 hours. The reaction mixture waspoured into the ice water (200 g) and extracted with ethyl acetate (200mL×2). The organic layer was dried over anhydrous Na₂SO₄. Theconcentration of the solvent gave a oily residue, which was purified bycolumn chromatography on silica gel (hexane/ethyl acetate=4/1 to 3/1) togive a solid compound. The solid compound was recrystallized from ethylacetate-hexane to give the subject compound (5.16 g).

(3) Preparation ofspiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione

2-bromo-3-cyanopyridine (2.96 g) and 1,4-cyclohexanedionemonoethyleneketal (3.47 g) were dissolved in anhydrous tetrahydrofuran(38 mL). After being cooled to −78° C., n-butyl lithium (1.5 M hexanesolution, 12.64 mL) was added and the mixture was stirred at −78° C. for30 minutes. The reaction temperature was allowed to rise up to the roomtemperature. The reaction mixture was poured into water (40 mL) andextracted with ethyl acetate (100 mL×3). The organic layer was driedover anhydrous MgSO₄. The concentration of the solvent gave a residue,which was recrystallized from ethyl ether-hexane to give iminoethercompound (2.93 g). This compound was dissolved in acetone (5 mL) and 2Nhydrochloric acid (30 mL). The solution was refluxed for 2 hours. Aftercooling, 2N sodium hydroxide aqueous solution was added to the reactionmixture to adjust pH to 4. The whole was extracted with ethyl acetate(100 mL ×3). The organic layer was dried over anhydrous MgSO₄. Theconcentration of the solvent gave a residue, which was recrystallizedfrom ether-hexane to give the subject compound (1.07 g).

(4)Preparation ofcis-4′-hydroxyspiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one

Spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-3,4′-dione (1.6 g) wassuspended in tetrahydrofuran (37 mL). After being cooled to 0° C.,lithium tert-butoxyaluminium hydride (1.0M tetrahydrofuran solution,9.58 mL) was added dropwise to the mixture. After the mixture wasstirred at 0° C. for 90 minutes, 1N hydrochloric acid was added toadjust pH to 2. The mixture was extracted with ethyl acetate (100 mL×4).The organic layer was dried over anhydrous MgSO₄. The concentration ofthe solvent gave the subject compound (1.58 g).

(5) Preparation oftrans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile

Cis-4′-hydroxyspiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-3-one (1.58g) and triethylamine (1.81 mL) were dissolved in chloroform (28 mL).After being cooled to 0° C., methanesulfonyl chloride (0.67 mL) wasadded thereto. The mixture was stirred at room temperature for 2 hour3and then poured into the saturated sodium bicarbonate aqueous solution(50 mL). The whole was extracted with chloroform (100 mL×3). The organiclayer was dried over anhydrous MgSO₄. The concentration of the solventgave a oily residue, which was purified by column chromatography onsilica gel (hexane/ethyl acetate=2/1 to 1/2) to give a solid compound.The solid compound was recrystallized from ethyl acetate-hexane to givethe desired mesylate compound (2.03 g). This compound was dissolved inanhydrous dimethylformamide (30 mL), and triethylammonium cyanide (3.2g) was added thereto. The mixture was stirred at 100° C. for 3 hours.After being cooled, the reaction mixture was poured into water (100 mL).The whole was extracted with ethyl acetate (100 mL×3). The organic layerwas dried over anhydrous MgSO₄. The concentration of the solvent gave aoily residue, which was purified by column chromatography on silica gel(hexane/ethyl acetate=3/1 to 2/1) to give a solid compound. The solidcompound was further recrystallized from ethyl ether-hexane to give thesubject compound (515 mg).

(6) Preparation oftrans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid

Water (6.6 mL) and concentrated sulfuric acid (2.2 mL) were added totrans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carbonitrile(515 mg). The mixture was refluxed for 13 hours. After the reactionmixture was cooled to 0° C., 4N sodium hydroxide aqueous solution wasadded to adjust pH to 4. The crystal precipitated was collected byfiltration. The crystal was washed with water, ethanol as well asdiisopropyl ether and then dried. The subject compound (500 mg) wasobtained.

¹H-NMR (300 MHz, DMSO-d₆, δ ppm): 1.73-1.80(2H, m), 1.81-1.94(2H, m),1.99-2.08(2H, m), 2.14-2.22(2H, m), 2.64-2.68(1H, m), 7.63(1H, dd,J=7.8, 4.8 Hz), 8.28(1H, dd, J=7.8, 1.5 Hz), 8.89(1H, dd, J=4.8, 1.5Hz).

(7) Preparation oftrans-N-(4-benzoylphenyl)-3-oxospiro-[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

trans-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxylicacid (26 mg) and 4-aminobenzophenone (20 mg) were dissolved in anhydrouspyridine (1 mL). 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (29 mg) was added thereto. The mixture was stirred at roomtemperature for 18 hours.

The reaction mixture was poured into water (10 mL). The whole wasextracted with ethyl acetate (30 mL×3). The combined organic layer wasdried over anhydrous MgSO₄. The concentration of the solvent gave anoily residue, which was purified by column chromatography on silica gel(hexane/ethyl acetate=3/1 to 2/1) to give a solid compound. The solidcompound was further recrystallized from ethyl acetate-hexane to givethe subject compound (30 mg) as colorless crystals (melting point214-216° C.)

Employing the procedure substantially as described in Example 90-(7),but substituting the appropriate amines for 4-aminobenzophenone used inExample 90-(7), compounds of Examples 91 to 95 were prepared.

Example 91trans-N-[1-(3.5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 269-271° C.

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 6.68 338 7.62 288 13.42 1202 14.22 69314.36 1880 15.48 965 16.40 652 16.92 1240 17.00 1232 18.82 1258 19.30690 20.02 908 20.12 932 20.26 515 21.56 663 22.80 560 22.90 755 23.12538 23.34 520 23.42 502 23.88 1342 25.10 2087 26.70 722 28.64 348 28.98272 29.66 273 31.42 273 31.94 315 32.08 353 34.06 293 36.02 267

Above powder X-ray diffraction analysis data were measured by the sameconditions as Example 32.

Example 92trans-3-oxo-N-[2-phenyl-4-pyridyl]spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 221-223° C.

Example 93trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 240-242° C.

Example 94trans-3-oxo-N-(1-phenyl-3-pyrrolyl)spiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 214-217° C.

Example 95trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 210-212° C.

Employing the procedure substantially as described in Example 57-(6),but substituting the appropriate amines for 4-aminobenzophenone used inExample 57-(6), compounds of Examples 96 to 98 were prepared.

Example 96trans-3-oxo-N-(I-phenyl-3-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 200-202° C.

Example 97trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 223-225° C.

Powder X-ray diffraction

2 θ (degrees) Intensity (cps) 8.14 1612 11.58 613 11.86 4470 12.60 147213.20 1208 13.30 975 15.86 1913 16.32 1665 17.72 2347 18.66 1482 18.762192 19.38 647 19.42 805 19.68 4470 19.76 3805 20.60 2302 21.46 169822.26 1375 22.34 1550 23.10 1422 23.88 588 24.48 697 24.66 3807 24.766918 25.28 992 25.38 1390 26.14 447 26.74 1853 27.50 2855 28.62 94328.70 975 30.58 1747 31.22 543 33.68 670 33.78 918

Above powder X-ray diffraction analysis data were measured by the sameconditions as Example 32.

Example 98trans-N-[1-(3-fluorophenyl)-4-pyrazolyl]-3-oxospiro-4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 176-178° C.

Employing the procedure substantially as described in Example 62-(6),but substituting the appropriate amines for 4-aminobenzophenone used inExample 62-(6), compounds of Examples 99 to 106 were prepared.

Example 99trans-3-oxo-N-(]-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 249-250° C.

Example 100trans-N-[1-(4-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 254-257° C.

Example 101trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 239-241° C.

Example 102trans-3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 221-223° C.

Example 103trans-3-oxo-N-(5-phenyl-3-isoxazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 259-261° C.

Example 104trans-3-oxo-N-(6-phenyl-3-pyridyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 249-251° C.

Example 105trans-3-oxo-N-(2-phenyl-3-thiazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 278-280° C.

Example 106trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide

melting point 232-233° C.

Formulation example 1

20.0 grams of compound of Example 1, 417 grams of lactose, 80 grams ofcrystalline cellulose and 80 grams of partial α-starch were blended witha V-cone blender. To the mixture was added 3.0 grams of magnesiumstearate and the whole was blended. The blended powder was compressedinto 3000 tablets by conventional procedure so t:hat each tablet has aweight of 150 mg and 7.0 mm in diameter.

The content of one tablet with a weight of 150 mg

the compound of Example 1 5.0 mg lactose 104.25 mg crystalline cellulose20.0 mg partial α-starch 20.0 mg magnesium stearate 0.75 mg

10.8 grams of hydroxypropylcellulose 2910 and 2.1 grams of polyethyleneglycol 6000 were dissolved in 172.5 grams of purified water. To thesolution was dispersed 2.1 grams of titanium oxide to provide a coatingliquid. 2500 tablets prepared in Formulation example 1, was subjected tospray-coating with the coating liquid using HICOATER-MINI to provide afilm coated tablet with a weight of 155 mg.

The content of one tablet (155 mg)

the tablet prepared in the Formulation example 1 150 mghydroxypropylcellulose 2910 3.6 mg Polyethylene glycol 6000 0.7 mgtitanium dioxide 0.7 mg

Compounds of the present invention exhibit NPY antagonistic activitiesand are useful as agents for the treatment of various diseases relatedto NPY, for example, cardiovascular disorders such as hypertension,nephropathy, heart disease, vasospasm, arteriosclerosis and the like,central nervous system disorders such as bulimia, depression, anxiety,seizure, epilepsy, dementia, pain, alcoholism, drug withdrawal and thelike, metabolic diseases such as obesity, diabetes, hormone abnormality,hypercholesterolemia, hyperlipidemia and the like, sexual andreproductive dysfunction, gastro-intestinal disorder, respiratorydisorder, inflammation or glaucoma, and the like.

What is claimed is:
 1. A compound represented by the general formula(I):

wherein Ar¹ represents an aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, loweralkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkylene optionally substituted with oxo, and a group represented byformula of —Q—Ar²; Ar² represents an aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl; n represents 0 or 1; Q represents asingle bond or carbonyl; T, U, V and W each independently represent anitrogen atom or a methine group which may have a substituent selectedfrom the group consisting of halogen, lower alkyl, hydroxy and loweralkoxy, wherein at least two of which represent said methine group; Xrepresents nitrogen; Y represents an imino which may be substituted witha lower alkyl, or oxygen; and a salt or ester thereof.
 2. The compoundof claim 1, wherein the aryl in Ar¹ is phenyl.
 3. The compound of claim1, wherein the heteroaryl in Ar¹ is pyrrolyl, imidazolyl, pyrazolyl,thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-thiadtiazolyl,pyridyl, pyrazinyl, pyrimidinyl, 1,2,4-triazinyl, benzoxazolyl,benzothiazolyl, quinolyl or pyrido[3,2-b]pyridyl.
 4. The compound ofclaim 1, wherein each of T, U, V and W is a methine which may have asubstituent selected from the group consisting of halogen, lower alkyl,hydroxy and lower alkoxy.
 5. The compound of claim 4, wherein each of T,U, V and W is a methine which may be substituted with halogen.
 6. Thecompound of claim 1, wherein one of T, U, V and W is nitrogen.
 7. Thecompound of claim 1, wherein Y is an unsubstituted imino or oxygen. 8.The compound of claim 1, wherein Y is oxygen.
 9. The compound of claim 1which is represented by the general formula (I-a):

wherein Ar¹ represents an aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, loweralkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkylene optionally substituted with oxo, and a group represented byformula of —Q—Ar²; Ar² represents an aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl;, Q represents a single bond orcarbonyl; R¹ represents hydrogen or halogen.
 10. The compound of claim9, wherein the aryl in Ar¹ is phenyl.
 11. The compound of claim 9,wherein the heteroaryl in Ar¹ is imidazolyl, pyrazolyl, isoxazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyrimidinyl, quinolyl orpyrido[3,2-b]pyridyl.
 12. The compound of claim 1, which isN-(4-benzoylphenyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide,N-(7-methyl-2-quinolyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,N-(4-benzoylphenyl)-2-methyl-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide,N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-N-(7-methyl-2-quinolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(4-acetylphenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-[1-(2-quinolyl)-4-imidazolyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-N-[5-(2-methyl-1-propenyl)-2-pyrazinyl]-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-[1-(7-benzo[b]furanyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-[1-(3-difluoromethoxyphenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-[4-(2-pyridylcarbonyl)phenyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(3,4-dichlorophenyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-[1-(3-chlorophenyl)-4-imidazolyl]-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-phenyl-2-thiazolyl)spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-[5-(2-pyridyl)-2-pyrazinyl]spiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,3,4-dihydro-N-(4-methyl-2-benzothiazolyl)-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(5-chloro-2-benzoxazolyl)-3,4-dihydro-3-oxospiro[isoquinoline-1(2H),4′-piperidine]-1′-carboxamide,N-(4-benzoylphenyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-(7-methyl-2-quinolyl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(3-phenyl-5-isoxazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-3-pyrazolyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(4-chlorophenyl)-3-pyrazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-[5-(3-quinolyl)-3-pyrazolyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-[5-(3-trifluoromethylphenyl)-2-pyrimidinyl]spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-chlorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-(7-difluoromethoxypyrido[3,2-b]pyridin-2-yl)-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(5-phenyl-1,2,4-thiadiazol-3-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-{1-[3-(2-hydroxyethyl)phenyl]-4-imidazoly}-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[4-(1-ethyl-2-imidazolyl)phenyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[1-(3-methoxyphenyl)-4-imidazolyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,6-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,6-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,5-fluoro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,5-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-(4-benzoylphenyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,3,4-dihydro-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,N-(5-benzoyl-2-pyrazinyl)-3,4-dihydro-3-oxospiro[1H-2-benzopyran-1,4′-piperidine]-1′-carboxamide,N-[5-(4-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-(5-(3-hydroxyphenyl)-2-pyrazinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,4-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,7-fluoro-3-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,6-ethyl-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,or6-hydroxy-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.13. The compound of claim 1, which is3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.14. The compound of claim 1, which is3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.15. The compound of claim 1, which isN-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.16. A process for producing a compound of the general formula (I-1):

wherein Ar¹ represents an aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, loweralkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkylene optionally substituted with oxo, and a group represented byformula of —Q—Ar²; Ar² represents an aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl; Q represents a single bond orcarbonyl; T, U, V and W each independently represent a nitrogen atom ora methine group which may have a substituent selected from the groupconsisting of halogen, lower alkyl, hydroxy and lower alkoxy, wherein atleast two of which represent said methine group; n and Y have the samemeaning as described hereinafter; and a salt or ester thereof, whichcomprises: reacting a compound of the general formula (II):

wherein Ar^(1p) represents an aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, nitro, lower alkyl, halo(lower)alkyl, cyclo(lower)alkyl, loweralkenyl, lower alkoxy, halo(lower)alkoxy, lower alkylthio, loweralkanoyl, lower alkoxycarbonyl, a group of formula: —Q^(p)—Ar^(2p), andan optionally protected, lower alkylene optionally substituted with oxo,hydroxy(lower)alkyl or carboxyl group; Ar^(2p) represents an aryl orheteroaryl which may be substituted, the substituent being selected fromthe group consisting of halogen, cyano, lower alkyl, halo(lower)alkyl,lower alkoxy, halo(lower)alkoxy, di-lower alkylamino, lower alkanoyl,aryl, and an optionally protected, hydroxy(lower)alkyl, hydroxy or loweralkyl amino group; Ar³ represents a phenyl which may be substituted byhalogen or nitro; Q^(p) represents a single bond or optionally protectedcarbonyl; with a compound of formula (III):

wherein n represents 0 or 1; t, u, v and w each independently representa nitrogen atom or a methine group which may have a substituent selectedfrom the group consisting of halogen, lower alkyl, lower alkoxy andoptionally protected hydroxy, wherein at least two of which representsaid methine group; Y represents an imino which may be substituted witha lower alkyl, or oxygen atom; to provide a compound of formula (IV-1):

wherein Ar^(1p), n, t, u, v, w and Y have the same meaning as describedabove; optionally followed by elimination of a protecting group. 17.Neuropeptide Y receptor antagonist which comprises a compound of thegeneral formula (I):

wherein Ar¹ represents an aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, loweralkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkylene optionally substituted with oxo, and a group represented byformula of —Q—Ar²; Ar² represents an aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl; n represents 0 or 1; Q represents asingle bond or carbonyl; T, U, V and W each independently represent anitrogen atom or a methine group which may have a substituent selectedfrom the group consisting of halogen, with a lower alkyl, hydroxy andlower alkoxy, wherein at least two of which represent said methinegroup; X represents nitrogen; Y represents an imino which may besubstituted with lower alkyl, or oxygen; and a salt or ester thereof.18. A method of the treatment of bulimia, obesity or diabetes, whichcomprises administering a therapeutically effective amount of a compoundof the formula (I):

wherein Ar¹ represents an aryl or heteroaryl which may be substituted,the substituent being selected from the group consisting of halogen,nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl, lower alkenyl, lower alkoxy, halo(lower)alkoxy, loweralkylthio, carboxyl, lower alkanoyl, lower alkoxycarbonyl, loweralkylene optionally substituted with oxo, and a group represented byformula of —Q—Ar²; Ar² represents an aryl or heteroaryl which may besubstituted, the substituent being selected from the group consisting ofhalogen, cyano, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,hydroxy, lower alkoxy, halo(lower)alkoxy, lower alkylamino, di-loweralkylamino, lower alkanoyl and aryl; n represents 0 or 1; Q represents asingle bond or carbonyl; T, U, V and W each independently represent anitrogen atom or a methine group which may have a substituent selectedfrom the group consisting of halogen, lower alkyl, hydroxy or loweralkoxy, wherein at least two of which represent said methine group; Xrepresents nitrogen; Y represents an imino which may be substituted witha lower alkyl, or oxygen; or a salt or ester thereof.
 19. Apharmaceutical composition for the treatment of bulimia, obesity ordiabetes which comprises a pharmaceutically effective amount of acompound of claim 1 together with a pharmaceutically acceptableadditive.